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PHYSIOLOGICAL REVIEWS
Vol. 80, No. 3, July 2000
Printed in U.S.A.
Corticotropin Releasing Hormone and Proopiomelanocortin
Involvement in the Cutaneous Response to Stress
ANDRZEJ SLOMINSKI, JACOBO WORTSMAN, THOMAS LUGER, RALF PAUS, AND SAMUEL SOLOMON
I.
II.
III.
IV.
Physiology of the Systemic Response to Stress: Role of the Hypothalamic-Pituitary-Adrenal Axis
The Skin as a Shock Organ for Environmental Stresses
Cutaneous Response to Stress: Local Neuroendocrine Signals
Corticotropin Releasing Hormone
A. CRH expression: intracranial
B. CRH expression: peripheral
C. CRH expression: skin
V. Corticotropin Releasing Hormone Receptors
A. CRH receptors: structure and function
B. CRH receptors: skin
VI. Proopiomelanocortin
A. POMC expression: intracranial
B. POMC expression: peripheral
C. POMC expression: skin
VII. Skin as a Target for Proopiomelanocortin Peptides
A. Melanocortin receptors
B. Opioid receptors
C. Phenotypic effects of POMC peptides
VIII. Regulation of the Cutaneous Corticotropin Releasing Hormone-Proopiomelanocortin System
A. UVR
B. Cytokines
C. Hair cycle
D. Disease states
E. Cellular metabolism mediators
F. Glucocorticoids
IX. Physiological Significance of Cutaneous Production of Corticotropin Releasing Hormone
and Proopiomelanocortin
X. Hypothesis on an Organized System Mediating Skin Responses to Stress
A. Hypothesis
B. Background to the organization and function of the SSRS
C. Functional organization of SSRS
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Department of Pathology, Loyola University Medical Center, Maywood; Department of Medicine, Southern
Illinois University, Springfield, Illinois; Department of Dermatology, Ludwig Boltzmann Institute of Cell
Biology and Immunobiology of the Skin, University of Munster, Munster; Department of Dermatology,
University Hospital Eppendorf, University of Hamburg, Hamburg, Germany; and Department of Medicine
and Biochemistry, McGill University and Royal Victoria Hospital, Montreal, Quebec, Canada
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Slominski, Andrzej, Jacobo Wortsman, Thomas Luger, Ralf Paus, and Samuel Solomon. Corticotropin
Releasing Hormone and Proopiomelanocortin Involvement in the Cutaneous Response to Stress. Physiol Rev 80:
979 –1020, 2000.—The skin is a known target organ for the proopiomelanocortin (POMC)-derived neuropeptides
␣-melanocyte stimulating hormone (␣-MSH), ␤-endorphin, and ACTH and also a source of these peptides. Skin
expression levels of the POMC gene and POMC/corticotropin releasing hormone (CRH) peptides are not static but
are determined by such factors as the physiological changes associated with hair cycle (highest in anagen phase),
ultraviolet radiation (UVR) exposure, immune cytokine release, or the presence of cutaneous pathology. Among the
cytokines, the proinflammatory interleukin-1 produces important upregulation of cutaneous levels of POMC mRNA,
POMC peptides, and MSH receptors; UVR also stimulates expression of all the components of the CRH/POMC
system including expression of the corresponding receptors. Molecular characterization of the cutaneous POMC
www.physrev.physiology.org
0031-9333/00 $15.00 Copyright © 2000 the American Physiological Society
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SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
Volume 80
gene shows mRNA forms similar to those found in the pituitary, which are expressed together with shorter variants.
The receptors for POMC peptides expressed in the skin are functional and include MC1, MC5 and ␮-opiate, although
most predominant are those of the MC1 class recognizing MSH and ACTH. Receptors for CRH are also present in
the skin. Because expression of, for example, the MC1 receptor is stimulated in a similar dose-dependent manner
by UVR, cytokines, MSH peptides or melanin precursors, actions of the ligand peptides represent a stochastic
(predictable) nonspecific response to environmental/endogenous stresses. The powerful effects of POMC peptides
and probably CRH on the skin pigmentary, immune, and adnexal systems are consistent with stress-neutralizing
activity addressed at maintaining skin integrity to restrict disruptions of internal homeostasis. Hence, cutaneous
expression of the CRH/POMC system is highly organized, encoding mediators and receptors similar to the hypothalamic-pituitary-adrenal (HPA) axis. This CRH/POMC skin system appears to generate a function analogous to the
HPA axis, that in the skin is expressed as a highly localized response which neutralizes noxious stimuli and attendant
immune reactions.
sors such as bursts of radiation (solar, thermal),
mechanical energy, or chemical and biological insults.
Because of its functional domains and structural diversity, the skin must have a constitutive mechanism for
The vertebrate brain is endowed with the functional
control of the endocrine system, which proceeds through
highly organized structures. This complex neuroendocrine function involves a myriad of pathways and humoral
mediators that are characteristically activated in response
to external (environmental) or internal changes sensed as
stressful. In chronic sustained stresses, the humorally
mediated involvement of the hypothalamic-pituitary-adrenal (HPA) axis is most prominent. Activation of this pathway by the stress-sensoring central circuits or the central
action of proinflammatory cytokines proceeds through
the hypothalamic production and release of corticotropin
releasing hormone (CRH), which stimulates pituitary
CRH receptors (5, 27, 110, 118, 232, 313, 421, 430) (Fig. 1).
CRH enhances the production and secretion of the anterior pituitary-derived propiomelanocortin (POMC) peptides melanocyte stimulating hormone (MSH), ACTH, and
endorphin (17, 110, 208, 267, 268) (Fig. 1). Upon release
into the systemic circulation, ACTH reaches the adrenal
gland and activates the MC2 receptors (MC2-R), inducing
thereby the production and secretion of corticosterone
(rodents) or cortisol (humans). These are powerful antiinflammatory factors that counteract the effect of stress
and buffer tissue damage. Moreover, the same steroids act
to terminate the stress response by interacting directly
with central nervous system (CNS) or anterior pituitary
receptors to attenuate CRH and POMC peptide production (110, 444). The underlying purpose of this adaptive
response is the stabilization and restoration of general
homeostasis (27, 42, 110, 208, 232, 267, 268, 415).
II. THE SKIN AS A SHOCK ORGAN FOR
ENVIRONMENTAL STRESSES
The skin, the largest body organ, is strategically located as a barrier between the external and internal environments, being permanently exposed to noxious stres-
FIG. 1. Systemic response to stress. The systemic response to stress
is activated by environmental/dyshomeostatic signals and biological
insults and is sensed by the central nervous system and the immune
system, respectively. The main mediator of the response is the hypothalamic-pituitary-adrenal axis (HPA). CRH, corticotropin releasing hormone; POMC, proopiomelanocortin; ACTH, adrenocorticotropic hormone; CA, catecholamines.
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I. PHYSIOLOGY OF THE SYSTEMIC RESPONSE
TO STRESS: ROLE OF THE HYPOTHALAMICPITUITARY-ADRENAL AXIS
July 2000
CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
III. CUTANEOUS RESPONSE TO STRESS:
LOCAL NEUROENDOCRINE SIGNALS
Whereas spatially and temporarily the responses to
stress of skin and CNS may be totally dissociated, their
similarity in functional relevance raises the possibility of
shared mediators. In this regard, it is known that mammalian skin, a well-characterized target for the POMC-derived
ACTH and MSH peptides, does contain POMC (220, 376, 438,
FIG. 3. Chemical mediators and postulated pathways of the functional arm of the skin CRH/POMC system. URC, urocortin; CRH-Rs, CRH
receptors; Rs, catecholamine receptors; MSH, melanocyte stimulating
hormone; ␤-END, ␤-endorphin; MC-Rs, melanocortin receptors; END-R,
endorphin receptors; 3?, possible stimulatory effect.
445). It has been further shown that the skin has the intrinsic
capability to actually produce POMC as well as CRH peptides and to also express the corresponding receptors. Cutaneous modulation of CRH and POMC production could be
mediated by proinflammatory cytokines, as is the case at the
systemic level. Thus the skin expresses an equivalent of the
HPA axis that may acts as a cutaneous defense system,
operating as coordinator and executor of local responses to
stress (Figs. 2 and 3) (362, 365, 376, 378).
Against the background above, we review evidence
documenting production and regulation of POMC and CRH
peptides, with expression of the corresponding receptors in
mammalian skin. Cutaneous mechanism regulating CRH
and POMC gene expression are compared with their central
homologs, and the function of local CRH and POMC derived
peptides is discussed within the context of the skin response
to stress. Information is provided on the experimental characterization of receptors for CRH and POMC peptides in
skin cells, regulation of their expression, and definition of
signal transduction pathways. Potential interactions within
the epidermal and follicular keratinocyte compartments occurring between the cutaneous equivalent of the hypothalamic-pituitary axis and the skin immune and pigmentary
systems are analyzed against experimental data and clinical
information already available. This review ends by setting
the stage for future research, basic and clinical, on cutaneous mediators in response to physical, chemical, or biological stressors.
IV. CORTICOTROPIN RELEASING HORMONE
A. CRH Expression: Intracranial
FIG. 2. Cutaneous response to stress. The CRH/POMC system is the
integrator and coordinator of the local response to environmental and
dyshomeostatic (internal) stimuli.
CRH, the most proximal element of the HPA axis, has
been already sequenced and its gene cloned (348, 413,
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dealing with those stressors while cellular/tissue damage
is still localized and of low magnitude, i.e., before triggering the systemic response. Ideally, such a defense mechanism should possess stress-sensoring capability of very
high sensitivity, because of the relatively low intensity of
the continuous pleiotropic physicochemical and biological insults affecting the skin. Thus the skin stress response mechanism may be envisioned as efficiently recording fluctuating environmental information; once a
critical threshold is reached, this would trigger an organized biological response. Hence, this cutaneous stress
response mechanism must be efficient, self-regulated in
intensity and field of activity, and endowed with the capability of differentiating environmental noise from biologically relevant signals (365, 376, 378). Those properties
imply continuous recognition and integration of appropriate signals, fast response to activation, and high degree of
specificity, all to rapidly reestablish tissue homeostasis
(Fig. 2). Desirable responses could involve, for example,
the stimulation of local biosynthetic pathways for the
manufacturing of buffering molecules to counteract the
damaging effect of physical, biological, or chemical insults (Fig. 3) (365, 376, 378, 382).
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and, through neurons projecting to the pituitary, CRH is
involved in osmotic regulation not connected with stress
(5, 267). In anterior pituitary corticotrophs, CRH regulates
POMC gene activity and production/release of ACTH,
␤-endorphin, and MSH peptides (5, 166, 267, 268). In
addition to the hypothalamus, CRH is produced in other
areas of the brain (5, 166). CRH production has even been
shown in the anterior pituitary, where it may act as a
paracrine stimulator of POMC production, as a growth
factor for corticotrophs, and as a modulator of expression
of the CRH-R1 gene (132, 239, 309, 413, 433). CRH is also
involved in functional modulation of the immune system
(27, 180, 268a, 331, 392, 394, 418, 430), the reproductive
system (100, 267, 297, 301), and the cardiovascular system
(19, 112, 267, 316, 320), and it acts as a major catabolic
peptide in the hypothalamus, inhibiting food intake, increasing energy expenditure, and producing sustained
weight loss (165).
B. CRH Expression: Peripheral
The CRH gene is widely expressed in extracranial
tissues but at levels much lower than in hypothalamus.
Expression of the gene has been detected in endometrium, placenta, uterus, ovary, testes, spleen, immune system, pancreas, liver, stomach, small and large bowel,
adrenal gland, thyroid gland, and skin (13, 27, 46, 87, 94,
100, 180, 184, 195, 253, 267, 268, 268a, 298 –303, 305, 318,
321, 335, 344, 355, 359 –361, 394, 398, 418, 430, 432, 456).
Peripheral processing of pro-CRH into CRH appears to be
similar at the peripheral and central levels, as shown in
placenta, endometrium, uterus, and immune system (49,
297, 301, 398, 456). In addition to its regulation by similar
factors as in the brain (100, 166, 267, 268, 297, 299, 301,
305, 332, 416, 430, 456), CRH production in peripheral
tissue is also enhanced by prostaglandins, epidermal
growth factor, and platelet growth factor and decreased
by nitric oxide (NO) and progesterone (297, 299, 301, 305,
319, 456). Accumulating evidence indicates that CRH produced in uterus and placenta may play an important role
in the normal progression of pregnancy (235, 297, 301,
456). CRH is a potent immunomodulator; depending on
cellular target, CRH can inhibit or stimulate local immune
function (9, 142, 195, 268a, 305, 334, 418, 421, 430). CRH
can modify vascular functions (19, 116, 267, 316, 320) and
also act as a local growth factor (239, 245, 357, 379, 417,
433). Expression of the CRH-related urocortin gene with
production of urocortin peptide has also been documented in peripheral tissues such as placenta, uterus,
immune system, stomach, small and large bowel, pancreas, adrenal gland, testis, heart, and skin (18, 262, 263,
298, 380).
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427). Most recently, a family of CRH-related peptides has
been identified in mammals, which shares high homology
with CRH, and includes urocortin, amphibian sauvagine,
and fish urotensin I (97, 436). The corresponding genes
have also been cloned (344, 348, 413, 454).
The CRH gene is composed of two exons separated
by an intron (344, 348, 413). The first exon encodes most
of the 5⬘-untranslated region in the mRNA, while the
second exon contains the prohormone sequence and the
3⬘-untranslated region. CRH transcripts in the rodent and
human brain are ⬃1.4 and 1.5 kb long, respectively (348,
413). The 3⬘-flanking region contains four polyadenylation
addition signals (AATAAA). The 5⬘-flanking region contains DNA sequences responsible for tissue specific expression, second messenger binding, and glucocorticoid
regulation sites (166, 267, 268). Translation of exon 2
generates the 196-amino acid (aa)-long prepro-CRH, in
which the first 26 aa represent the signal peptide, cleaved
in the rough endoplasmic reticulum to generate pro-CRH(27O196) (49, 166, 294, 295). Unmodified pro-CRH(27O196) has 18 kDa molecular mass, that increases to 23
kDa after posttranslational modifications (294, 295). Endoproteolytic processing of pro-CRH within the transGolgi-network and secretory granules generates the final
41-aa-long (4.7 kDa) CRH peptide (166, 267, 268, 294, 295).
Additional intermediates may include the 16-kDa NH2terminal pro-CRH, pro-CRH-(125O149; 8 kDa), and proCRH-(125O151; 3 kDa). The enzymes involved in this
process are the convertases PC1 and PC2 (49).
Expression of the CRH gene is controlled by cAMPdependent protein kinase A (PKA), calcium/calmodulindependent protein kinase and diacylglycerol-dependent
protein kinase C (PKC) pathways (4, 98, 166, 267, 268,
430). In addition, transcription factors associated with
cytokine signaling can also activate the CRH promoter
(395). A list of stimulators of CRH production at the
central level includes the neurotransmitters serotonin,
acetylcholine, histamine, norepineprine, and epinephrine
(166, 192, 199, 261, 267, 268); the neuropeptides arginine
vasopressin (AVP), ANG II, neuropeptide Y, cholecystokinin, activin, and enkephalin; the cytokines interleukin
(IL)-1, IL-6, and tumor necrosis factor (TNF)-␣, which can
also stimulate CRH production (27, 50, 166, 267, 268, 305,
395, 418, 420, 421); and leptin (165). Among the negative
regulators of CRH production, the most important are
glucocorticoids; estrogens and GABA also share this activity (166, 267, 268, 305, 395, 418). In addition, secretion
of CRH is inhibited by dynorphin, substance P, somatostatin, and galanin (166).
CRH is produced predominantly in the paraventricular nucleus (PVN) of the hypothalamus and delivered into
portal capillaries converging in the anterior lobe of the
pituitary (5, 166, 267, 268, 418). In addition, autonomic
neurons of the PVN projecting to the brain stem and
spinal cord supply CRH to the sympathoadrenal system
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
C. CRH Expression: Skin
1. Rodent
(321). Corresponding serum concentrations of CRH-IR
were 8.6 fmol/ml during anagen III and 5.6 fmol/ml in
telogen (321). Surprisingly, however, the corresponding
CRH mRNA was consistently below the limit of RT-PCR
detectability in any of the different phases of hair cycle
(telogen, anagen, and catagen) (360). Because CRH-IR is
found in the nerve bundles and perifollicular neural network B throughout the entire hair cycle, and CRH concentrations are higher in tissue than serum (321), we have
proposed that in the mice CRH is imported into the skin,
entering through descending (afferent) nerves. Such
transport would provide a mechanism to precisely regulate domains of local CRH-dependent POMC production
(321, 357, 360).
The lack of expression of the CRH gene in skin was
further confirmed by the results of RT-PCR assays repeated with larger number of cycles and followed by
Southern blot hybridization to CRH cDNA; again, these
tests failed to show CRH mRNA in mouse skin, despite its
presence in brain control (104). Thus the abundance of
CRH-IR in the skin and its nerve bundles in the absence of
cutaneous CRH gene expression imply that at least in the
FIG. 4. Expression of CRH and CRH-R1 antigens throughout hair growth cycle in mice. CRF, CRH; APM, arector pili
muscle; DP, dermal papila; E, epidermis; FBN, follicular neural network B; HS, hair shaft; IRS and ORS, inner and outer
root sheaths, respectively; Mel, melanocytes; SG, sebaceous gland. [From Roloff et al. (321), with permission from the
FASEB Journal.]
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CRH was first detected in the skin by immunocytochemistry as CRH immunoreactivity (CRH-IR) in the
C57BL6 mouse, in the pilosebaceous unit of the hair
follicle and epidermis (360). CRH-IR was further localized
to keratinocytes of the basal epidermis, the outer root
sheath (ORS), and the matrix region of developing hair
follicles (321). In hair follicles, the highest intensity of
stain was seen during the anagen IV/VI stages and the
lowest levels in catagen and telogen skin (321). CRH-IR
was also found in the nerve bundles and perifollicular
neural network B throughout the entire hair cycle (321). A
schematic drawing of hair cycle coupled CRH and CRH-R
expression in murine skin is presented in Figure 4.
Actual identification of CRH was accomplished with
two separate techniques based on reverse-phase HPLC
combined with CRH RIA (321, 357). Tissue levels of CRH
measured by RIA showed hair cycle-dependent fluctuation being highest in anagen II/IV skin (67 fmol/g wet wt)
and lowest in catagen and telogen skin (36 fmol/g wet wt)
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mice, CRH may reach the skin through descending nerves
that target well-defined compartments (360). An alternative explanation, that skin cells could express a hitherto
undetected CRH variant or a related CRH gene, is undergoing current testing. In this regard, immunoreactivity
corresponding to the related peptide urocortin was detected at varying levels in mouse skin; the highest concentrations were observed in telogen and the lowest in
late anagen VI skin (380).
2. Human
V. CORTICOTROPIN RELEASING HORMONE
RECEPTORS
A. CRH Receptors: Structure and Function
So far, two distinct genes encoding the CRH receptor
(CRH-R) family (CRH-R1 and CRH-R2) have been cloned
(73, 77, 78, 190, 194, 207, 217, 242, 296, 391, 426, 437). Both
receptor groups share high sequence homology, ⬃70%,
and belong to the family of seven transmembrane segments proteins coupled to the Gs signaling system.
CRH-R1 and CRH-R2 differ in pharmacological ligand profile and predominant tissue distribution; e.g., CRH-R1 has
predominantly been found in the pituitary and different
regions of the brain (5, 74, 78, 289, 310, 437), whereas
CHR-R2 has been isolated from brain, heart, and skeletal
muscle (73, 190, 194, 207, 217, 296, 310). Alternatively
spliced forms have also been identified, e.g., CRH-R1
(variant ␤) that contains 29 additional aa in the first
intracellular loop and a variant c having a deletion of 120
bp coding for 40 aa from the extracellular NH2-terminal
domain (78, 388). Three CRH-R2 spliced variants ␣, ␤, and
␥ that differ in their NH2-terminal domains and anatomical distribution have been identified (190, 194, 207, 217,
242, 296, 391, 426). In humans CRH-R2␣ and CRH-R2␤ are
expressed in peripheral tissues and in brain, whereas in
rodents, CRH-R2␣ is found predominantly in brain and
CRH-R2␤ in the periphery (5, 74, 388). So far, CRH-R2␥
variant has been only detected in brain (194). Human and
rat CRH-R1 genes contain 14 and 13 exons, respectively
(330, 419), whereas the human CRH-R2␣ gene contains 12
exons (207). In addition to CRH receptors, CRH binding
proteins of 322 aa have been characterized; these are
partially associated with plasma membranes or circulate
in the blood (74, 185, 218, 293, 307). CRH binding proteins
have high affinity for CRH and are postulated to inactivate
extracellular CRH, thus preventing its interaction with
receptors. This would be the mechanism for neutralization of the large amounts of circulating CRH present
during pregnancy (74, 185, 218, 235, 293, 300, 307).
The CRH signal is transduced into cAMP and calciumactivated metabolic pathways via interaction with the CRHR (5, 74, 100, 267, 268, 388). Activation of adenylate cyclase
induces production of cAMP, and subsequently of PKAdependent pathways. CRH-R activation of phospholipase C
induces production of inositol trisphosphate (IP3), which
leads to activation of PKC-dependent pathways. There are
data suggesting that CRH signal transduction is directly
coupled to calcium channels (109, 198, 388). The CRH signal
is transduced more efficiently into stimulation of cAMP
production through CRH-R1 than CRH-R2 (74, 442). For
example, CRH and urocortin are more potent than sauvagine and urotensin I in activation of adenylate cyclase activity
through CRH-R1, although urocortin, sauvagine, and urotensin I are more potent than CRH in the stimulation of cAMP
production through CRH-R2 (74, 442). The affinity of CRH
for CRH-R1 is similar to that of urocortin and sauvagine,
whereas CRH-R2 affinity for CRH is significantly lower
than for urocortin, sauvagine, and urotensin I (5, 74, 388).
CRH-R have so far been identified in adrenal glands,
testes, ovaries, prostate, kidney, liver, gut, spleen, circulating immune cells, synovium, heart, skeletal muscle,
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The CRH gene, although not expressed in mice skin,
is nevertheless clearly demonstrable in human skin by
RT-PCR amplification of the predicted 413-bp transcript
representative of the CRH exon 2 (355, 359, 361). In the
latter experiments, the sources of human skin RNA tested
were biopsy specimens of scalp, compound melanocytic
nevus and basal cell carcinoma, and cultured cell lines of
normal and malignant melanocytes and squamous cell
carcinoma (355, 359, 361). Melanoma and squamous cell
carcinoma cells showed a CRH mRNA transcript 1.5 kb
long by Northern blot hybridization (361). CRH peptides
were also detected in facial skin, cultured human melanocytes, HaCaT keratinocytes, squamous cell carcinoma,
and melanoma cells after RP-HPLC separation followed
by monitoring of the eluted fractions with specific antiCRH RIA (355, 361). Most recently, expression of CRH
gene was found in a large panel of cultured melanocytes,
nevocytes, and melanoma cells, with the highest intensity
in malignant melanocytes (121). Indirect immunofluorescence studies localized the CRH antigen to keratinocytes
of the epidermis and hair follicle, dermal blood vessels,
skeletal muscle, and nerve bundles of human scalp (357).
Expression of the related urocortin gene and production
of the corresponding urocortin peptide was also shown in
human skin (380).
In normal melanocytes, production of CRH peptide
could be stimulated with ultraviolet radiation B (UV-B;
wavelength 290 –320 nm) (355); and in melanoma and
squamous cell carcinoma cells, CRH production responded to forskolin, an agent that raises intracellular
cAMP levels (361). Conversely, dexamethasone inhibited
CRH peptide production in the same cell systems (361).
However, despite noticeable changes in CRH peptide production, the level of the corresponding CRH mRNA remained unchanged under each one of the tested conditions, suggesting posttranscriptional regulation.
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
BP) that may inactivate or inhibit local CRH signaling in
placenta, amnion, chorion, and maternal decidua (293,
297–301). Near term there is a rapid surge in circulating
CRH in human pregnancy that coincides with a decrease
of plasma CRH-BP levels (72, 235, 293).
B. CRH Receptors: Skin
1. Rodent
Searching for mRNA coding for CRH receptors using
RT-PCR amplification of RNA isolated from C57BL6
mouse skin has clearly shown the predicted 407-kb product representative of the CRH-R1 mRNA (360). The transcript was present throughout the entire hair cycle, even
during the telogen phase (360). In the hairless mice
CRH-R1 mRNA was also detected; RT-PCR assay with
Southern blot hybridization to murine CRH-R1 cDNA
showed its presence in the epidermis (357). Studies with
full thickness skin in the C57BL6 mice showed a 2.7-kblong CRH-R1 mRNA transcript by Northern hybridization;
it was readily detectable in anagen skin and below detectability in telogen skin (360). In the same model, CRH-R1
protein was localized by indirect immunofluorescence to
keratinocytes of the ORS, hair matrix, dermal papilla of
anagen VI hair follicles, keratinocytes of inner root sheath
(IRS), and ORS of early catagen; in contrast, skin immunoreactive CRH-R1 was very low in telogen skin (Fig. 4)
(321). These results suggest that both transcription and
translation of the CRH-R1 gene are hair cycle dependent.
Most recently, RT-PCR assays using primers described in
Reference 318 identified a 615-bp fragment common to
the ␣- and ␤-variants of the mouse CRH-R2 cDNA (318;
Fig. 5). Sequencing of the cloned segment showed an
almost perfect match with the published mouse CRH-R2
genebank sequence; the single difference was a change of
G to A found at position 675 in the known sequence (base
7 in the experimental sequence). This base permutation
did not affect the amino acid sequence in the encoded
peptide fragment that was exactly the same as the known
sequence.
CRH did exhibit specific binding to skin, as detected
by autoradiography with a 125I-[Tyr]-ovine CRH (oCRH)
tracer (321). CRH binding was localized to keratinocytes of hair follicles and the epidermis and dermal panniculus carnosus (mostly to dermal muscles; Ref. 321).
Displacement curve analysis revealed a single high-affinity binding site with a dissociation constant (Kd) of 3.62
nM and maximum binding (Bmax) of 2.42 amol/mm2 of
scanned skin section. Control determinations in rat pituitary revealed a single high-affinity binding site with a
similar Kd of 1.53 nM, but with larger number of binding
sites, e.g., Bmax was 18.1 amol/mm2 (321). During the hair
cycle, 125I-[Tyr]-oCRH specific binding to isolated cell
membranes was at the same level in telogen, anagen III,
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uterine myometrium, vascular endothelium, arterial
smooth muscle, endometrium, placenta, and skin (5, 13,
19, 74, 86, 100, 139, 150, 151, 163, 181, 190, 200, 267, 268,
296, 297, 301, 302, 305, 318, 320, 321, 334, 338, 357, 388,
391, 409, 410, 456). Molecular and pharmacological characterization of CRH receptors have shown that CRH-R2 is
predominantly expressed in peripheral tissues, e.g., heart,
skeletal muscle, smooth muscle of arterial wall, vascular
endothelium, uterus, placenta, and immune cells (74, 139,
151, 163, 190, 200, 297, 301, 318, 334, 388, 391). Notwithstanding, CRH-R1 has been also detected in intrauterine
tissue, placenta, and immune cells (94, 139, 181, 297, 301,
318, 396, 409). The signal transduction pathway activated
through peripheral CRH receptors is coupled to the stimulation of cAMP production and subsequent activation of
PKA (74). However, involvement of calcium-activated
pathways by phospholipase C or membrane-bound calcium channels has also been reported (19, 109, 186 –188,
198, 242, 357, 388). In addition, the NO/cGMP-dependent
pathway appears to mediate CRH-R activated vasodilation in human fetal-placental circulation (86), and a sustained vasodilator effect of CRH and sauvagine on rat
mesenteric artery through stimulation of NO production
has been reported (19).
CRH-R located in heart and vasculature mediate the
inotropic, vasodilatory, and antiedema effects of CRH or
CRH-related peptides (19, 74, 112, 268, 316, 320, 440, 441),
whereas receptors present on immune cells mediate complex immune/inflammatory responses (27, 305, 418, 430).
Although central CRH (neuroendocrine) effects are immunoinhibitory (27, 268, 305, 418), in peripheral tissues
CRH effect on immune balance is complex (27, 142, 180,
268a, 305, 331, 333–335, 418, 430, 440, 441). In fact, CRH
may have an opposite immunoactivating effect in periphery, by stimulating proinflammatory reactions (180, 305,
418, 430), although an anti-inflammatory effect for exogenously applied CRH has also been described (142). Paez
Pereda et al. (268a) showed that CRH can either stimulate
or inhibit IL-1 production depending on monocyte activation status; therefore, it is likely that activation-dependent
signal transduction through CRH receptors may explain
sometimes contradictory phenotypic effects in immune
cells. Locally produced CRH may regulate steroid production in gonads and adrenal glands via a paracrine mechanism of action (56, 102, 103, 150, 387). In placenta and
uterus, CRH receptors that include CRH-R1 and CRH-R2
are involved in maintenance of pregnancy as well as
initiation and maintenance of labor (235, 297, 301, 456). In
this setting, CRH receptors are activated through paracrine or autocrine mechanisms by locally produced CRH
or urocortin (297, 301). This action requires precise timeand tissue-restricted differential expression of CRH receptors in intrauterine tissues (86, 87, 94, 297–303, 318,
319, 396, 456). Regulation of CRH activity may be also
achieved by the production of CRH binding protein (CRH-
985
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SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
and anagen VI skin (321, 357). It is possible that autoradiography may have detected both CRH-R1 and CRH-R2
because of the low specificity of the technique. Because
the distribution of CRH-R1 is hair cycle dependent,
CRH-R1 may predominate in epidermal and follicular keratinocytes, whereas CRH-R2 gene expression would predominate in extrafollicular compartments such as panniculus carnosus.
A) CRH EFFECT ON HAIR GROWTH AND EPIDERMIS. CRH participation in the regulation of hair growth was evaluated
in a well-characterized skin organ culture system (272,
273), in which DNA synthesis in epidermal and dermal
compartments reflects predominantly proliferation of keratinocytes, either epidermal or follicular (357). In this
model, addition of CRH to telogen and anagen IV skin was
found to stimulate DNA synthesis in epidermal keratinocytes, without measurable effect on the dermal compartment (357). However, in anagen II, CRH had the opposite
activity on epidermal DNA synthesis, exerting an inhibitory effect, whereas dermal DNA synthesis was enhanced
(357). These experiments suggest strong hair cycle restriction in the expression of CRH actions on epidermal
and follicular keratinocyte proliferation. Thus experiments with exogenous CRH show variable effects depending on the cellular population targeted and on the
hair cycle-dependent expression of CRH-related recep-
tors. Contributing factors in determining the effect of
exogenous CRH could include the endogenous production of CRH and CRH-related molecules and the CRHactivated production of ACTH and MSH.
Preliminary in vivo experiments in mice showed that
CRH released slowly from subcutaneous implants placed
in the direct vicinity of telogen hair follicles effectively
resulted in follicular arrest with extended telogen (resting) stage (R. Paus, K. Fechner, and L. Mecklenburg,
unpublished data). It is not yet clear whether hair follicle
cycle arrest is a direct action of CRH or whether it simply
reflects a systemic effect of serum corticosterone. High
serum levels of CRH could substantially raise corticosterone levels through stimulation of the HPA axis (444).
High systemic levels of glucocorticosteroid would clearly
suffice as the explanation for the profound anagen-inhibitory effect of CRH implants (cf. Refs. 272–274).
B) CRH EFFECTS ON THE VASCULAR AND IMMUNE SYSTEMS.
Intradermally injected CRH induces local mast cell degranulation in rats and mice (409). This effect is dose
dependent, mediated by the amidated form of CRH, and
inhibited by the nonpeptide CRH-R1 antagonist antalarmin. Because CRH-R1 mRNA has been detected in
mast cells, those effects may be mediated through
CRH-R1 (409). CRH-induced degranulation of mast cells is
accompanied by increased vascular permeability (reduced by treatment with H1-receptor antagonists), leading
to the suggestion that this cutaneous effect of CRH may
be primarily addressed at enhancing local vascular permeability (409). However, others have found that direct
topical application of CRH to cutaneous or mucosal tissue
had instead vasoconstrictive and anti-inflammatory effects (134, 237, 440). Particularly interesting are the studies of CRH on animal models of tissue injury (134, 237,
333–335, 440, 441). Thus when CRH is injected subcutaneously or intravenously to rats with thermal injury, fluid
accumulation is decreased by ⬎50% in injured skin of
treated animals, independent of the functional activity of
the HPA axis. This action has been explained by CRHinduced decrease in negative interstitial fluid pressure on
traumatized tissues, thereby reducing edema. Moreover,
local injection of CRH reduced doxorubicin-induced inflammation in the eyelid of rabbits and decreased the
severity of skin injury (237). In the latter study, CRH did
not alter vascular permeability but reduced the expected
acute influx of monocytes and macrophages and protected the skin overlying the injection site, substantially
reducing the extent of injury. Other studies have shown
that in the rat urocortin has significantly higher potency
than CRH, inhibiting heat-induced cutaneous edema
(422). Because ␣-helical CRH-(9O49) reversed the inhibition of edema produced by either urocortin or CRH, at
doses that did not affect ACTH secretion, it has been
suggested that those effects are mediated through
CRH-R2 (422). Additional CRH effects on inflammation
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FIG. 5. Expression of the CRH receptor type 2 (CRH-R2) gene in the
skin of C57BL6 mouse. Primers sequence and RT-PCR conditions for
amplification of the 615-bp fragment common to the ␣- and ␤-variants of
the mouse CRH-R2 cDNA were performed as described in Reference
318. This fragment was sequenced commercially using the BigDye chemistry kit and a 377XL DNA sequencer from Perkin Elmer/Applied Biosystems (Commonwealth Biotechnologies, Richmond, VA). Two internal
primers, inverses of each other and with sequences GTCAATCCTGGCGAGGACGA and TCGTCCTCGCCAGGATTGAC, were used for sequence determination. The cloned segment differed from the published
mouse CRH-R2 genebank sequence only in a single base (G to A change
at position 675 in the known sequence; base 7 in the experimental
sequence). Lane A, DNA ladder; lane B, anagen III; lane C, anagen IV;
lane D, anagen VI.
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
2. Human
In human skin biopsy specimens, CRH-R1 mRNA was
identified by RT-PCR followed by Southern blot hybridization and found in normal scalp, compound nevus, basal
cell carcinoma, and perilesional facial skin (357, 359, 361).
The CRH-R1 gene was also expressed in normal and
malignant melanocytes (121, 357, 359, 361) and keratino-
cytes (359, 361); the expression was upregulated by UVB
irradiation or 12-O-tetradecanoylphorbol 13-acetate
(TPA) treatment (359). CRH-R1 gene expression was high
in melanoma and squamous cell carcinoma cells (121,
361).
A) BIOCHEMICAL CHARACTERIZATION OF CRH RECEPTORS. Human melanoma cells and HaCaT keratinocytes exhibit
specific binding sites for CRH; application of CRH or of
the related sauvagine or urocortin peptides induces rapid
and significant increases in intracellular calcium (109,
357). The effect appears to be specific for these peptides,
since the neuropeptides ␤-endorphin, ␣-MSH, and ACTH,
which also interact with G protein-linked receptors, had
either no or minimal effects (357). The calcium stimulatory activity in human melanoma cells is higher for CRH
than urocortin or sauvagine peptides, being detected already at concentrations as low as 10⫺12 and 10⫺10 M in a
dose-dependent manner (109). Similar to hamster melanoma, the CRH induced intracellular calcium accumulation in these human cell lines was inhibited by the CRH
antagonist ␣-helical CRH-(9O41) and by extracellular calcium depletion with EGTA (109). Because human melanoma cells express CRH-R1 mRNA, it was postulated that
the above effects are mediated through CRH-R1 (109).
Studies on the A 431 human squamous cell carcinoma
cells showed that the structurally related peptides CRH,
sauvagine, urotensin I, and mystixin-7 and mistyxin-11
stimulated cytosolic calcium accumulation and IP3 production (186 –188). These pharmacological studies suggest therefore that the increases in cytosolic calcium are
due to both calcium influx from the extracellular compartment, through calcium channels coupled to CRH receptors and pertussin toxin-sensitive G proteins, and to
mobilization of intracellular calcium through intracellular
calcium-independent increase in IP3 (186 –188). CRH and
CRH-related peptides can also stimulate cAMP production and tyrosine phosphorylation in A 431 carcinoma
cells, albeit with a different pattern for each group of
peptides tested (186 –188), suggestive of differential CRH
receptor subtype activation (187). Most recently, we have
provided evidence for the existence of CRH receptors in
human keratinocytes and defined cAMP-mediated CRHstimulated pathway in these cells, with demonstrable inhibitory activity on cell proliferation (379).
CRH receptors were also identified in human dermal
fibroblasts, where two binding sites with different affinities were found (115). The high-affinity binding site had
Kd of 20 ⫾ 0.22 pM and Bmax of 1.95 ⫾ 0.22 fmol/mg
protein, and the low-affinity class of receptor had Kd of
160 ⫾ 17 nM and Bmax of 2.38 ⫾ 0.27 fmol/mg protein
(115). CRH receptor expression was accompanied by the
phenotypic effect of CRH blockage of the IL-1␣ stimulated
prostacyclin (PGI2) and PGE2 production (114, 115). Because CRH inhibits IL-1␣-stimulated PGI2 and PGE2 synthesis in bovine aortic endothelial cells through probable
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include antinociceptive actions and acceleration of
wound healing (333–335, 440, 441).
There is indirect evidence for CRH activity on the
local regulation of blood flow through effects on the
cutaneous vasculature. These would be mediated by interaction with CRH receptors present on smooth muscle
of the arterial wall. For example, vasorelaxing effects
have been shown in rat mesenteric arteries that imply
mediation via CRH-R2 on vascular smooth muscle (320).
Other studies have demonstrated the presence of CRH
binding sites of high and low affinity on endothelial cells:
Kd of 2 ⫾ 0.2 ⫻ 10⫺10 and 1.77 ⫾ 0.14 ⫻ 10⫺6 M and Bmax
of 0.79 ⫾ 0.095 and 0.97 ⫾ 0.12 fmol/mg protein, respectively, for high- and low-affinity binding sites (116). The
expression of those receptors was accompanied by an
inhibitory effect of CRH on IL-1␣-induced prostacyclin
and prostaglandin synthesis through inhibition of phospholipase A2 and cyclooxygenase (114 –116). Most recently, a dual vasodilatory effect of CRH and sauvagine on
mesenteric artery was described: a short direct effect on
smooth muscle, followed by sustained endothelium dependent vasodilation (19). The last effect was associated
with stimulation of NO production. Therefore, by analogy
with the mesenteric bed (19, 114, 116, 320) and vasculature in the placenta and brain (86, 316, 338), it is possible
that CRH would also act through a similar pathway on
cutaneous vascular cells, endothelial or smooth muscle,
with possible effects on local inflammation, hemostasis,
and/or coagulation.
C) CRH EFFECTS ON MALIGNANT MELANOCYTES. The hamster
melanoma cell line provided further insight into the mechanism of CRH action in the skin (109, 357). This cell
system expresses the CRH-R1 gene and CRH binding
sites. The melanoma CRH-R1 mRNA transcript is ⬃2.5 kb
long, being 0.2 kb shorter than that detected in normal
skin (357). CRH had demonstrable biological effects that
consisted of a rapid and dose-dependent increase in intracellular calcium concentration. This effect was reduced by preincubation with the CRH antagonist ␣-helical
CRH-(9O41) and actually inhibited by depletion of extracellular calcium with 3 mM EGTA. Therefore, CRH signal
transduction appears to be coupled, at least partly, to
activation of calcium channels (109). The CRH-related
peptides sauvagine and urocortin also induced increases
in intracellular calcium concentration but at concentrations ⬃1,000-fold higher.
987
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SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
VI. PROOPIOMELANOCORTIN
B. POMC Expression: Intracranial
The pituitary gland has been recognized as an important source of melanotropic factors (6, 14), defined as ␣and ␤-MSH and ␤-endorphin (cf. Refs. 110, 141, 143, 201,
444). The structures of the POMC gene and of the POMC
protein have been well established (cf. Refs. 75, 110, 141,
143, 444). The POMC gene is expressed predominantly in
the anterior pituitary where it comprises ⬃30% of all
mRNA (282). POMC mRNA concentration is one to two
orders of magnitude higher in pituitary than in brain (17).
In general, mammals trascribe only one POMC gene
per haploid genome (99), although the mouse genome
contains two nonallelic POMC ␣- and ␤-genes (425). The
mouse POMC ␣-gene is transcribed in pituitary and brain;
it is located on chromosome 12 and shares high homology
with human, bovine, and rat POMC genes (424). The
POMC ␤-gene has ⬍90% aa sequence homology (predicted from cDNA sequence) with ␣-POMC (425). The POMC
␤-gene is not expressed in pituitary, has the characteristics of a pseudogene, and is located on chromosome 19
(425). Lower vertebrates including lamprey, fish, and
frogs also express two forms of POMC gene that have
different degree of homology depending on the species
(12, 402). The human POMC gene is located on chromosome 2 (25).
The mammalian POMC gene contains three exons
and two introns; exon 1 corresponds to the 5⬘-untranslated mRNA; exon 2 contains a part of the 5⬘-untranslated
mRNA, sequences of the signal peptide, and start se-
quences of the NH2-terminal fragment (NT); and exon 3
codes for the COOH terminus of NT, joining peptide (JP),
ACTH, ␤-lipotropin (LPH), and for 3⬘-untranslated mRNA
(17, 25, 59, 75, 99, 143, 170, 222). In the pituitary and brain,
the primary transcripts are spliced out to generate a
POMC mRNA of ⬃1.1 kb (17, 25, 99, 170, 222). Shorter and
longer POMC transcripts also exist but are found only in
extrapituitary tissues that include skin (17, 76, 84, 91, 99,
167, 353, 371). The POMC mRNA size heterogeneity has
been explained by alternative splicing, variation in the
length of the poly(A)⫹ tail, or use of alternate transcription initiation sites (17, 76, 84, 91, 99).
POMC mRNA is translated into a single 30-kDa protein product, the precursor of ACTH, endorphins, melanotropins (MSH), and lipotropins (LPH) (25, 59, 170, 383).
These neuropeptides are differentially generated through
successive cell-specific processing steps and postranslational modifications that include endo- and exopeptidase
cleavage, amidation, and acetylation (7, 8, 17, 20, 25, 59,
170, 383). As indicated in Figure 6, posttranslational processing of POMC yields a large number of biologically
active peptides. POMC is processed in the corticotrophs
of the anterior pituitary to form ACTH, ␤-LPH, and NT,
with smaller amount of ␥-LPH and ␤-endorphin (59). Further processing occurs in the intermediate lobe: NT to
␥-MSH, ACTH to ␣-MSH and corticotrophin-like intermediate lobe peptide (CLIP), and ␤-LPH to ␤-MSH, ␤-endorphin, ␤-endorphin-(1O26) and ␤-endorphin-(1O27). All of
the peptides formed in this manner undergo amidation,
mono- and diacetylation, phosphorylation, glycosylation,
and methylation before processing of POMC is completed
(7, 8, 17, 20, 25, 59, 170, 383). In the pituitary, the biosynthetic processing of the POMC precursor starts with specific cleavage by the convertases PC1 and PC2 at the
post-pairs of basic residues (Lys-Arg) and (Arg-Arg) (59,
90, 345, 455). The convertase PC1 cleaves POMC to produce a 16-kDa NT, the JP, and the COOH-terminal peptides ACTH and ␤-LPH with some ␤-endorphin (25, 59).
PC1 is expressed solely in corticotrophs determining their
commitment to the production and secretion of ACTH. In
melanotrophs, the coexpression of convertases PC1 and
PC2, as well as the expression of carboxypeptidase E, and
the amidating and N-acetylating enzymes determine that
this cell type produces essentially ␣-MSH and ␤-endorphin (25, 59, 90, 106, 170, 270, 345, 383). PC2 convertase
cleaves the first 14 aa of the ACTH sequence to generate
ACTH-(1O14)OH peptide and ␤-LPH to ␤-MSH and ␤-endorphin (25, 59). The ACTH-(1O14)OH after COOH-terminal amidation generates desacetyl-␣-MSH, a step required for biologic activity (25, 59, 383). Interestingly,
whereas subsequent ␣-N-acetylation at the NH2 terminus,
that results in ␣-MSH, enhances the melanocyte stimulating bioactivity of the tridecapeptide (25, 59, 383), and
acetylation of ␤-end inhibits its opioid activity (25, 59).
The O-acetylation of ␣-MSH forms N,O-diacetyl-␣-MSH. It
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inhibition of phospholipase A2 and cyclooxygenase (116),
it is highly possible that a similar regulatory mechanisms
may be operative in dermal endothelial cells of human
skin.
B) CRH EFFECTS ON CELL PROLIFERATION. CRH has heterogeneous effects on cell proliferation. Thus, in HaCaT keratinocytes, cell growth is inhibited after addition of
10⫺11–10⫺8 M CRH to the culture medium (379). In contrast, in melanoma cultures, the effect is biphasic in that
short-term incubation (6 h) with CRH (10⫺10–10⫺8 M)
inhibits DNA synthesis in either serum-containing or serum-free media, whereas long-term incubation (3– 4 days)
at high CRH concentration (10⫺7–10⫺6 M) stimulates the
growth of melanoma cells (357, A. Slominski and B.
Zbytek, unpublished data). Both stimulation and inhibition of cell proliferation by CRH have been described in
AT-t20 pituitary cells (239, 433), whereas cell growth is
inhibited in CRH-treated mammary cancer cells (417).
CRH at concentrations of 10⫺10–10⫺6 M had no effect on
melanin synthesis in cultured melanoma cells (Slominski
and Zbytek, unpublished data).
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
989
has been suggested that PC1 or PC2 may be also involved
in the generation of ␥-MSH peptides; however, the mechanism of the reaction and the potential involvement of
other enzymes remain to be clarified (90, 345).
Production and secretion of POMC peptides is organ
specific, and in the pituitary it is lobe specific and under
multihormonal control with main stimulatory input by
CRH and AVP, and inhibitory regulation by adrenal glucocorticoids (17, 25, 50, 59, 99, 110, 141, 170, 192, 222, 383,
439). Epinephrine also has ACTH stimulatory activity, and
the cAMP-PKA system appears to be the main intracellular signaling pathway for this pituitary action (10) that
stimulates ACTH secretion, similar to the effect of pituitary adenylate cyclase-activating peptide (PACAP) and
vasoactive intestinal polypeptide (VIP) (11). PACAP and
VIP enhance separately the CRH stimulation of the POMC
gene, but without additive effect. Other factors that stimulate production of POMC peptides by the anterior pituitary are PACAP, VIP, serotonin, oxytocin, ANG II, bradykinin, and leptin, whereas GABA decreases it (11, 17, 25,
59, 81, 124, 165, 170, 222, 243, 327, 383, 414). In the
intermediate pituitary, neither glucocorticoids nor CRH
has any effect on POMC gene expression, although CRH
can selectively induce release of ␣-MSH (17, 25, 59, 170,
222, 383). ␣-MSH release from the intermediate pituitary
is stimulated by ␤-adrenergic agonists, whereas negative
regulators of this process are dopaminergic and ␣-adrenergic agonists, PGE2, and branched amino acids (17, 25,
59, 170, 222, 329, 383).
The proinflammatory cytokines IL-1, IL-2, IL-6,
TNF-␣, and INF-␥ stimulate pituitary POMC gene expression and production of POMC peptides (17, 25, 27, 32, 33,
118, 170, 305, 313, 383, 421). However, the mechanism of
this regulation is complex. For example, IL-1 stimulates
POMC promoter activity in AtT-20 cells in a bimodal
manner (weak short-term effects followed by strong longterm effects) (182). A similar effect was found for TNF-␣;
IL-6 had a robust stimulatory long-term effect, whereas
INF-␥ had acute stimulatory effects followed by a marked
inhibitory effect. The effect of the cytokines on POMC
gene expression is mediated by the tyrosine phosphorylation cascade (182). IL-1, IL-6, and TNF-␥ can also significantly potentiate the stimulatory effect of CRH on POMC
expression (17, 25, 33, 118, 170, 305, 313, 383, 421). Leukemia inhibitory factor (LIF) can stimulate POMC gene
expression and secretion by corticotrophs (80), acting
synergistically with CRH to potentiate POMC transcription and production of ACTH (15). Most recently, it has
been proposed that LIF and IL-1␤ activate the suppressors
of cytokine signaling (SOCS) pathway, which would inhibit POMC gene expression and ACTH secretion, thus
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FIG. 6. Processing of POMC in the pituitary
gland and central nervous system. END, endorphin; N-TERM, NH2-terminal segment; JP, joining
peptide; LPH, lipotrophin; CLIP, corticotropinlike intermediated lobe peptide; I, dibasic amino
acid cleavage recognition site; O, glycosylation
sites; P, phosphorylation sites. [From Castro and
Morrison (59), by permission from Critical Reviews in Neurobiology.]
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SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
acting as a negative-feedback mediator in cytokine activity on the neuro-immuno-endocrine axis (16).
B. POMC Expression: Peripheral
of POMC in lymphoid tissues, perhaps due to the presence of distinct proteases that are selectively expressed in
LPS-treated B cells where a truncated form of ACTH is
detected (144). Neutrophils, however, have only been
shown to express a 9.5-kb POMC mRNA transcript and do
not release ␣-MSH (393). Recently, CRH was found to be
synthesized and released by lymphocytes where it upregulates POMC mRNA production (144, 305, 385, 393,
407). Cells in the monocytic lineage that contain POMC
and produce melanocortins include human peripheral
blood monocytes, epidermal Langerhans cells, cell lines
derived from myeloid malignancies (U937), and rodent
peritoneal macrophages (55, 206, 216, 225, 238, 240, 247).
Basal production of melanocortins by monocytic cells is
low but increases significantly upon stimulation with LPS,
mitogens (concanavalin A), or tumor promoters (phorbol
12-myristate 13-acetate) (224, 247). In addition to immunocompetent cells, other cells known to release immunomodulating cytokines such as cardiac muscle cells, fibroblasts, and keratinocytes have been found to synthesize
and release POMC peptides and thereby contribute to the
development of an immune response (220, 241, 337, 408).
In humans, increased production of POMC peptides
has been detected during the course of arthritis, in viral
and parasitic infections, and in inflammatory skin diseases such as atopic eczema (32, 61, 62, 135, 136, 144, 258,
259, 384, 443). ␣-MSH injected systemically has immunosuppressor activity blocking IL-6- and TNF-␣-induced fever, inhibiting the development of adjuvant-induced arthritis, and preventing endotoxin-induced hepatitis by
antagonizing various cytokines and chemokines (60, 61,
83, 152, 210), suggesting its participation in the immune
responses against viral infections. Indeed, POMC elements may bind POMC transcription factors present in
the human immunodeficiency virus-1 genome, in cytomegalovirus, and in some oncogenes (c-fes, MAT-1).
Therefore, signals known to mediate the activation of
POMC transcription factors such as corticotropin releasing factor, tumor promoters, or ultraviolet light may activate viruses or oncogenes and thus facilitate infection and
possibly tumor development (208). ␣-MSH also antagonizes the neuroendocrine effects of CRH and IL-1 (347,
423).
C. POMC Expression: Skin
MSH was the first POMC peptide detected directly in
the skin (411), which expresses the POMC gene and produces also ACTH and ␤-endorphin (cf. Refs. 220, 365, 376,
378, 445). POMC gene transcription and translation in the
mammalian skin was originally observed in the C57BL6
mice (370, 371). Subsequently, POMC gene expression has
been found in human skin, normal and pathological, and
in cutaneous cell culture systems (57, 67, 71, 96, 104, 107,
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Transcription and translation of the POMC gene have
been detected in most peripheral tissues including placenta, uterus, gonads, thyroid, pancreas, adrenals, gastrointestinal tract, lungs, spleen, immune system, and skin
(17, 27, 32, 33, 117, 170, 220, 226, 238, 258 –260, 297, 301,
305, 365, 376, 383, 445). These extracranial sites produce
shorter and longer POMC transcripts, in addition to the
1.1-kb message (17, 84, 91, 99, 167, 353, 371). That heterogeneity may represent alternative splicing, variation in
the length of the poly(A)⫹ tail, or use of alternative transcription initiation sites (76). It has been questioned
whether mRNA smaller than 1.1 kb are translatable, since
they lack the signal peptide that enables the end products
to exit the cell (85, 167). In this regard, a POMC mRNA of
only 0.8 kb found in placenta, testes, and ovary has been
associated with the production of secretory POMC peptides (cf. Refs. 3, 167, 301, 383). Furthermore, in vitro
assays have shown that short POMC transcripts can indeed be translated (85); possible mechanisms allowing
translocation of peptides and proteins lacking the signal
sequence have been recently described (197). It appears
that most tissues have the ability to produce POMC but at
levels much lower than in pituitary (17, 27, 32, 33, 59, 170,
297, 305, 376, 383, 456). In placenta and testes, production
of POMC peptides is stimulated by CRH (3, 297, 301, 302).
In the immune system, POMC expression and peptide
release are stimulated by CRH, AVP, lipopolysaccharide
(LPS), and IL-1 and inhibited by glucocorticoids (27, 33,
183, 305, 421).
Because of the significance of the immune system in
the skin (43), it could participate as a local site of production of the POMC peptides ␤-endorphin, ACTH, and
␣-MSH. In fact, full-length POMC transcripts have been
detected in splenic mononuclear cells (MNC), which process POMC to ACTH through the same pathway as in
corticotrophs (225). Also, lymphocytes and macrophages
form predominantly ␤-endorphin and ACTH-(1—9), with
smaller amounts of ACTH-(1O24), ACTH-(1O25), ACTH(1O26), and ␤-endorphin-(144O146). T lymphocytes of
human and murine origin as well as lymphoma-derived
T-cell lines both express POMC mRNA and release the
POMC peptides ␣-MSH and ACTH (55, 144, 224, 225, 259,
393). In human lymphocytes, POMC mRNA transcripts of
0.8, 1.2, and 1.5 kb have been detected (393). Similarly,
murine ␥/␦ epidermal T lymphocytes express a truncated
form of POMC and release ␣-MSH (108). The presence of
ACTH immunoreactivity has been clearly demonstrated in
rodents T-helper cells, cytotoxic T cells, and B cells (224).
There is also evidence suggesting differential processing
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
July 2000
1. Expression of POMC gene and production
of POMC peptides in skin cells
TABLE
Cell Type
POMC
mRNA
POMC Peptides
MSH, melanocyte stimulating hormone; LPH, lipotrophin; POMC,
proopiomelanocortin; ND, not done; NA, not applicable. * ␥-MSH is
present in transformed melanocytes. † Below detectability by immunocytochemistry. ‡ Below detectability by in situ hybridization and immunocytochemistry.
108, 122, 128, 131, 168, 169, 189, 211, 212, 215, 219, 223,
255, 337, 353, 354, 356, 359, 360, 363, 370, 371, 381, 408,
411, 446). Table 1 summarizes the expression of POMC
peptides in different cutaneous compartments.
1. Rodent
Immunoreactive ␣-MSH has been detected in rodent
skin from Wistar, Hooded, and Norwegian Brown rats,
gerbils, and hairless mice (411). Cutaneous ␣-MSH (mean
concentrations, expressed as ng/g wet tissue wt) has
ranged from a low of 0.3 (Norwegian Brown rat) to a high
of 3.2 (gerbils), values consistently lower than the corresponding hypothalamic and pituitary concentrations
(411). Nevertheless, the skin levels are similar to the
levels measured in extrahypothalamic-pituitary regions of
the brain (411). Skin ␣-MSH peptide concentrations are
unaffected by hypophysectomy, at least in rat, gerbil, and
mouse skin (411). Moreover, skin peptide concentration
is not modified by daily injection of ␣-MSH that increase
7- to 10-fold the ␣-MSH plasma levels of hypophysectomized or intact rats. Therefore, MSH peptides detected in
the skin are not of pituitary or plasma origin (411). Instead, these data and direct evidence obtained in the
C57BL6 mouse (see below) indicate that ␣-MSH present
in rodent skin is the result of local production. Our own
molecular studies in mouse skin have shown that the
POMC gene is actually transcribed, translated (371), and
further processed to the POMC peptides ACTH, MSH, and
␤-endorphin (122, 356, 371). Also, the hairless mice ex-
press POMC mRNA in skin, as shown by RT-PCR and
Northern blot hybridization of epidermal mRNA (G. Ermak and A. Slominski, unpublished data).
A) POMC GENE EXPRESSION AND POMC PEPTIDES PRODUCTION IN
C57BL6 MOUSE SKIN. The POMC transcript of C57BL6 mice
skin is 0.9 kb long, and the POMC protein, detected with
an anti-␤-endorphin antibody, has 30 –33 kDa molecular
mass (371). The truncated form of POMC mRNA has been
detected in epidermis and in epidermal Thy-1⫹ dendritic
cells in the C57BL6 mouse skin (107, 108). A combination
of Northern and Western blot analysis with immunocytochemistry detected both mRNA transcript and POMC protein during the active growth phase of the hair cycle
(anagen) (122, 356, 360, 371). Because POMC gene expression was not detected (371) or was very low (360) in the
resting phase of the hair cycle (telogen), the experiments
were interpreted as indicative of hair cycle-dependent
gene expression and thus raised the possibility of POMC
product involvement in skin appendage physiology (104,
273, 356, 368).
In additional studies, the exon 3 of the POMC transcript was found to be constitutively expressed in skin,
being low in telogen and significantly upregulated in the
growth phase of the hair cycle (anagen) (360). An attempt
to determine the size of POMC mRNA on anagen skin
using pituitary and brain RNA as standards give inconclusive results. This was due to the large discrepancy in
tissue gene expression (per unit of mRNA ), with levels at
least 10,000-fold higher in pituitary than skin. Nevertheless, a truncated 0.9-kb POMC transcript was still present
throughout the entire anagen, and an additional 1.1-kb
POMC transcript was detected in anagen IV (360). Another attempt was then made to detect full-length POMC
mRNA at a latter stage of the hair cycle (anagen VI skin)
(104), when melanogenic activity reaches its peak (368,
369, 373). RT-PCR amplification was performed with
primers spanning exons 1–3 and exons 2–3 (signal peptide
and coding region) or exon 3 (coding region only), followed by Southern hybridization to murine POMC cDNA.
Only a 475-bp transcript from exon 3 was detected; fragments of 810 and 738 bp corresponding to regions spanning exons 1–3 and exons 2–3 were present in pituitary
and brain controls but absent in anagen skin (104). Thus,
in anagen VI skin, the truncated 0.9-kb transcript may be
the sole or predominant POMC species (104), yet it is the
appearance of a 1.1-kb POMC transcript in anagen IV (day
5 after anagen induction) that correlates with the detection of a 30- to 33-kDa POMC protein on same day specimens; the POMC protein was not found in telogen or
during the preceding days of anagen development (371).
Therefore, selective expression of the 1.1-kb transcript
(during anagen IV) may be the predominant pathway that
leads to synthesis of the POMC protein in mouse skin
(104). Nevertheless, truncated POMC mRNA transcripts
may be translated (85), and peptides and proteins lacking
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Epidermal keratinocytes Present ␣-, ␤-, ␥-MSH, ACTH, ␤-endorphin,
␤-LPH
Follicular keratinocytes Present ␣-, ␤-MSH, ACTH, ␤-endorphin
Epidermal melanocytes Present ␣-, ␤-MSH,* ACTH, ␤-endorphin
Follicular melanocytes
ND
Absent†
Dermal nevocytes
Present ␣-, ␤-MSH, ACTH, ␤-endorphin
Sebocytes
Present ␣-, ␤-MSH, ␤-endorphin
Sweat gland cells
ND
␣-, ␤-, ␥-MSH
Endothelial cells
Present ␣-MSH, ACTH, ␤-endorphin
Langerhans cells
Present ␣-MSH, ACTH
Monocytes
Present ␣-MSH, ACTH
Macrophages
Present ␣-MSH, ACTH
Lymphocytes
Present ␣-MSH, ACTH
Fibroblasts
Present ND
Adipocytes
ND
ND
Skeletal muscle
ND
ACTH
Smooth muscle‡
Absent Absent
Nerves
NA
␣-, ␥-MSH, ACTH
991
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SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
and perifollicular nerves ending, although it is additionally expressed in keratinocytes of ORS and hair matrix
during anagen IV (273). POMC mRNA has been detected
by in situ hybridization localized to the the dermal sebaceous glands in skin from the anagen III-VI phase of the
hair cycle, whereas epithelial expression of the same
POMC mRNA, first detected in scattered keratinocytes of
the epidermis and ORS of hair follicles of anagen I, increases during progression to anagen VI (230, 231). The
convertases PC1 and PC2, present at very low levels in
epidermal keratinocytes of telogen skin, increase in anagen VI, with PC1 showing the greatest change (230). In the
pilosebaceous unit, only PC1 is detected in telogen skin,
whereas PC2 becomes detectable in anagen VI skin (230).
Thus a close temporal correlation exists between localization and intensity of POMC mRNA expression, expression of the POMC processing convertases PC1 and PC2,
and detection of POMC derived peptides.
B) POMC GENE EXPRESION AND POMC PEPTIDE PRODUCTION IN
RODENT MELANOMAS AND CELL CULTURE SYSTEMS. In the amelanotic rodent melanoma lines, Bomirski AbC1 hamster and
Cloudman S91 mouse clone 6, Northern hybridization
analysis detected POMC mRNA transcripts of 3.5, 1.5, and
⬃1–1.1 kb (353). Expression of POMC mRNA in both cell
lines correlated with detection of a 30-kDa POMC protein
by Western blotting and by cytoplasmic immunostaining
with antibodies against ␤-endorphin and ␥3-MSH (353,
367). These results indicate that hamster and mouse melanoma cells can transcribe and translate the POMC gene.
POMC mRNA production in the AbC1 line was stimulated
by exposure to L-DOPA (353). Of potential oncologic relevance, the amelanotic Bomirski tranplantable hamster
melanoma and melanotic variants are linked by common
origin (41, 353, 367). In comparative analysis, POMC
mRNA was expressed only in the rapidly growing amelanotic Ab variant, whereas POMC mRNA was not detected
in the two slower growing Ma and MI melanotic variants
(353). We have therefore suggested that in this system
POMC gene expression may represent an autoregulatory
mechanism whose expression stimulates progression to
the malignant phenotype (367).
The melanocytic cell lines that produce ␣-MSH include LND2 and different subclones of B16 and Cloudman
S19 melanomas, normal nontransformed (Melan A) and
ras transformed (LTRras11–3, PAGTori and PAGT5)
mouse melanocytes, and human melanoma lines (67, 71,
128, 223, 457). In the B16 melanoma line, immunoreactive
␣-MSH (␣-MSH-IR) has been further identified by RPHPLC as desacetyl-␣-MSH (223). The highest concentrations of ␣-MSH-IR were found in the least differentiated,
most metastatic melanoma cell lines and in ras-transformed melanocytes (223). In mice transplanted with various B16 melanomas, only the highly metastatic variant
was ␣-MSH positive, with the IR located predominantly in
the peripheral invading zones (457). This was in contrast
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the signal sequence may still be translocated (197). Thus
the 0.9-kb POMC mRNA cannot be entirely excluded as a
source of POMC peptides.
Glucocorticoids are the physiological suppressors of
pituitary POMC production (99, 110, 141, 170, 383, 444),
and correspondingly, the synthetic glucocorticoid dexamethasone attenuates POMC mRNA production in anagen
skin (104). Topical dexamethasone treatment is accompanied by decreased mRNA coding for the cutaneous MC1
(receptor for ␣-MSH) and for tyrosinase, and tyrosinase
activity is correspondingly decreased (104). Topical application of dexamethasone also produces massive catagen development and rapid inhibition of melanogenesis
(104, 273, 274, 372). Thus murine hair growth and attendant melanogenesis may be jointly regulated by local
POMC peptide production/MC1 receptor stimulation
(104), and suppression of this local pathway by glucocorticoids would explain the observed termination of both
hair growth and follicular melanogenesis.
In mouse skin extracts, the POMC products detected
by RP-HPLC coupled to specific RIA assays include ␤-endorphin, ␣-MSH, and ACTH peptides (122, 273, 356). Thus
accumulated evidence indicates that mouse skin produces POMC, which is then processed to its secretory
neuropeptides; triggering of this expression sequence
may be linked to hair cycle (122, 231, 273, 356, 360, 368,
371). Accordingly, ␤-endorphin concentrations increase
during anagen development, reach a peak in anagen VI,
and decline during follicle involution (catagen); the lowest levels are reached in the resting phase (telogen) (122,
371). The pattern for ACTH immunoreactivity is similar to
␤-endorphin, e.g., low levels in telogen with a rise during
anagen to a peak in anagen VI skin (356). These episodic
variations in local levels of POMC peptides also correlate
with expression of the convertases PC1 and PC2, from a
high level in anagen VI to being low in telogen (230). The
pattern of predictable intermittent cutaneous accumulation of ACTH, MSH, and ␤-endorphin peptides indicates
precise regulatory control that determines actual production rates; whether the peptides degradation rates are also
under regulatory control remains to be tested.
The differential expression of POMC products is not
only associated with functional changes (hair cycle
phase) but is also anatomically restricted (cellular compartment specific). In this regard, immunocytochemistry
studies have shown that ␤-endorphin staining is primarily
limited to sebocytes (Fig. 7), ACTH stain to epidermal and
ORS keratinocytes, and to skeletal muscle, whereas
␤-MSH stains follicular and epidermal keratinocytes,
sweat gland ducts, and sebocytes (122, 230, 231, 273, 356,
371). These immunostains also show the already mentioned temporal dependence on hair cycle phase, with
lowest levels in telogen and progressive increases to a
peak in anagen VI (122, 231, 371). ␣-MSH is detected
throughout the entire hair cycle mainly in nerve bundles
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
993
to levels below the limit of detectability of the assay in the
low metastatic F1 variant, which grows as a noninvading
tumor. Characterization of POMC mRNA from the S-91
melanoma cell line PS-1-HGPRT-1 showed three transcripts of ⬃6.5, 3.5, and 1.1 kb (71). These corresponded,
respectively, to nonspliced primary transcription product,
alternatively spliced product, and mature POMC. In the
same melanoma cell line, UVB stimulated POMC gene
expression and production and release of ACTH and
␣-MSH in a dose-dependent manner (71).
Because all of the above models of melanoma express MSH receptors, the observed production of POMC
peptides could represent an autostimulatory mechanism,
which accelerates growth and aggressive malignant behavior. The general trend is that POMC gene is more
actively transcribed, or produces more POMC-derived
␣-MSH in the least differentiated, most malignant hamster
and mouse melanoma cells and in ras-transformed melanocytes (223, 353, 367, 457). Deregulated intrinsic expression of the POMC gene appears then as a common factor
preceding malignant transformation of melanocytes
and/or melanoma progression to less differentiated faster
growing forms (223, 353, 367, 457). Thus local expression
of POMC peptides triggered by undetermined factors
could alter melanoma cell phenotype promoting tissue
invasion. POMC peptides would exert this action through
auto-, intra-, or paracrine mechanisms; alternatively,
POMC peptides may affect surrounding tissues such as
immune elements or vascular system to further promote
tumor growth and metastatic cascade.
In addition to being present in melanoma, POMC
peptides are also produced by several nonmelanoma rodent skin cell lines (71, 108, 220, 223). For example, the
immortalized (BALB/c) PAM 212 keratinocytes, in which
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FIG. 7. Hair cycle-associated expression of
␤-endorphin in sebaceous glands of the C57BL6
mouse. The ␤-endorphin antigen was localized
to the sebaceous glands by immunocytochemistry with anti-␤-endorphin antibody. Left: low
magnification (⫻100). a, Telogen; b, anagen I; c,
anagen II; d, anagen IV; e, anagen V. Right: high
magnification (⫻560) showing ␤-endorphin immunorectivity in individual glands. a, Anagen I;
b, anagen IV; c, anagen V; d, anagen V. [From
Slominski et al. (371), with permission from
Birkhaeuser Publishers.]
994
SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
production of ACTH and MSH is stimulated by UVB or
dibutyryl cAMP (71), and immune cells such as epidermal
Thy-1⫹ lymphocytes, Langerhans cells, and circulating
cells of monocytic lineage express the POMC gene and
produce POMC peptides (108, 220).
2. Human
446). In this regard, cultured keratinocytes and melanocytes produce POMC peptides and release ␣-MSH and
ACTH into the medium (67, 189, 337, 354, 446). Production of ␣-MSH and ACTH can be significantly upregulated
at the protein and mRNA levels upon treatment with
phorbol 12-myristate 13-acetate, IL-1, and UV light (67, 96,
219 –221, 337, 341, 342, 446).
A) EXPRESSION OF POMC GENE AND PRODUCTION OF POMC
PEPTIDES IN VIVO. Production of POMC peptides in vivo was
strongly suggested by the immunocytochemical studies
performed in skin biopsy specimens and cultured cells
and was supported by the corresponding detection of
POMC mRNA. In situ hybridization experiments with normal human skin showed strong POMC mRNA expression
in epidermal melanocytes and keratinocytes, whereas in
the dermis, POMC mRNA was detected at much lower
levels, in endothelial and perivascular cells (57). Thus
these studies confirmed previous work implicating epidermal and dermal cells as source of cutaneous POMC
peptides (57, 107, 168, 169, 189, 212, 219, 255, 337, 354,
359, 381, 389, 408, 438, 446). Of note, ␥-MSH-IR was shown
in nerve fibers in the basal layers of epidermis, in the
upper dermis, close to Merkel cells, in Meissner’s corpuscles, around ORS of the hair follicle, in nerve bundles of
the deep dermis, and to a lesser degree around sweat
glands and blood vessels (169, 212). Because POMC peptides have been detected in the circulating immune system (27, 32, 33, 169, 219 –221, 247, 305), together with
cutaneous nerves, they may represent additional sources
of POMC peptides in the skin.
Most resident skin cells express in situ ␣-MSH and
ACTH, ␤-MSH, ␤-endorphin, and ␥-MSH peptides (Table
1), arising from different portions of the POMC protein
precursor. The peptide nature of the immunocytochemically detected antigens was confirmed with RP-HPLC
analyses that did demonstrate the presence of desacetyl␣-MSH, mature ␣-MSH, and ACTH peptides in extracts of
human epidermis (438) and in perilesional and lesional
skin from areas of basal cell carcinoma (363). Thus these
analyses performed in biopsy specimens, in conjunction
with the cell culture studies, demonstrate that POMC
precursor protein is produced in situ, being processed
locally to the final secretory peptides. Expression of MSH
and ACTH was accompanied by epidermal expression of
the POMC processing enzymes PC1 and PC2 convertases,
with PC2 showing tendency to coexpress with ␣-MSH
(438). It therefore appears that POMC processing may be
cell type regulated similar to pituitary corticotrophs and
melanotrophs, i.e., skin cells may specialize in the production of either ACTH or ␣-MSH as initially proposed
(376).
The detection of POMC peptides in skin is common
to a broad spectrum of apparently unrelated conditions,
from the neoplastic melanocytic nevi, melanoma, basal
cell carcinoma, and squamous cell carcinoma to the in-
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MSH was initially detected as immunoreactivity in
extracts of normal human skin and identified by RP-HPLC
in isolated epidermis as the desacetyl-, monoacetyl-, and
diacetyl forms (411, 438); this established the background
for further studies on the local expression of POMC peptides. With the use of immunocytochemistry on frozen
sections of normal human skin, ␣-MSH was found in
epidermal melanocytes and Langerhans cells, and ACTH
was found in differentiating keratinocytes (438). Pathological specimens of human skin evaluated by immunocytochemistry also showed POMC-derived antigens in
dermal and epidermal compartments (381). The POMC
peptides expressed included ACTH, ␣-MSH, and ␤-endorphin, although a consistent pattern did not emerge (381).
In normal corporal skin (obtained after surgery), POMC
peptides were detected in dermis but not epidermis. Dermal POMC peptides were present in anagen hair follicles,
where they accumulated in keratinocytes of ORS and hair
matrix. In human scalp, POMC peptides were seen in both
epidermal and follicular keratinocytes (381). The possible
discrepancy with the results of Wakamatsu et al. (438),
who did detect POMC peptides in epidermis of normal
corporal skin, may be explained by the lower sensitivity
for detection in the Formalin-fixed paraffin-embeded tissues (381). Direct RIA analyses in normal human skin
showed that immunoreactive MSH levels were indeed
very low or below the level of detectability (214). The
same group found high MSH levels in melanoma lesions,
which, together with our detection of ACTH, ␣-MSH, and
␤-endorphin in a wide range of skin diseases suggest that
POMC peptide expression represents a disease-related
phenomenon (381). Such a possibility received strong
support from observations in keloids, a rather homogeneous primary reactive skin disorder, where POMC products were consistently detectable (10 of 11 cases) and
localized to keratinocytes and mononuclear cells (381).
Because POMC mRNA was detectable by RT-PCR in biopsy specimens from normal scalp, basal cell carcinoma,
and compound nevus, cutaneous POMC peptides appear
to originate from local production (359). Together these
findings suggest that POMC peptides are produced and
stored locally in lesional (especially reactive) skin cells as
a component of the cutaneous response to injury.
More recently, it was confirmed that human skin cells
could actually produce POMC peptides either in vivo (57,
168, 169, 211, 212, 220, 255, 363, 381, 438) or in cell culture
systems (67, 96, 107, 189, 337, 341, 342, 354, 359, 408, 438,
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
POMC spillover from the skin is also suggested by studies
in severe atopic dermatitis and psoriasis (125, 135, 136,
252). These patients showed increased serum ␤-endorphin levels; however, because of the previous immunocytochemical detection of POMC peptides in psoriatic skin
(381), it was suggested that circulating ␤-endorphin could
be generated, at least partly, in lesional skin (135).
POMC peptide production was evaluated by indirect
immunofluorescence in skin biopsies from 16 patients
with vitiligo lesions and 13 matched healthy controls
(212). Keratinocytes from control skin and from involved
and uninvolved skin of vitiligo patients expressed ␣-, ␤-,
and ␥3-MSH (212). MSH-IR was, however, higher in keratinocytes and extracellular compartments of involved vitiligo skin than in control skin. The adnexal structures
(sweat glands and pilosebaceus orifices) showed no difference in the intensity of stain (212). Plasma ␣-MSH
levels were similar in vitiligo and control patients,
whereas ␤-endorphin levels were higher in vitiligo, failing
to show the normal circadian rhythmic change (252).
B) EXPRESSION OF POMC GENE AND PRODUCTION OF POMCDERIVED PEPTIDES IN VITRO. Expression of the POMC gene has
been noted in cells of epidermal and dermal origin that
include normal melanocytes and keratinocytes (57, 66, 96,
107, 189, 219, 337, 354, 359, 438, 446), Langerhans cells
(247), fibroblasts (408), human dermal microvascular endothelial cells (HDMEC) (341, 342), circulating immune
cells (34, 35, 40, 41, 72, 258 –260), and malignant melanocytes and keratinocytes (67, 128, 354, 363, 411). Gene
expression was accompanied by detection of POMC-derived ACTH, ␣-MSH, and ␤-endorphin immunoreactivities
in cultured cells and culture medium. Characterization of
␣-MSH and ACTH peptides by RP-HPLC analyses of cell
extracts in normal and malignant melanocytes and in
keratinocytes showed multiple forms of POMC peptides
(128, 131, 337, 354, 363, 411, 438), which included ACTH(1O10), acetyl-ACTH-(1O10), ACTH-(1O17), ACTH(1O39), desacetyl-␣-MSH, and ␣-MSH (354, 363, 411, 438).
Western blot analyses have confirmed the production of
␤-LPH and ␤-endorphin in normal keratinocytes (446),
whereas normal melanocytes and squamous cell carcinoma cell ␤-endorphin was detected by RP-HPLC analyses combined with specific RIA assay (354). In melanoma
and squamous cell carcinoma cells, ACTH, ␣-MSH, and
␤-endorphin were determined by RP-HPLC-RIA (411); one
of the ACTH-IR peaks eluted at the same time as ACTH(1O13) (354). These observations suggested that processing of POMC to ␤-endorphin, ACTH, and ␣-MSH is a
constitutive property of skin cell type, regardless of
whether they are benign or malignant. Production of
POMC peptides in keratinocytes and melanocytes was
found to be under regulatory control, being stimulated by
UVB, selected cytokines, and other factors (47, 64, 67, 220,
337, 446) (see below). Also, HDMEC stimulated by UVB
and UVA produce and release ␣-MSH and ACTH (341,
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flammatory keloids, psoriasis, and scarring alopecia
(381). This finding suggests that deregulated local production of POMC may be a common reactive phenomenon in
cutaneous pathology (381), a possibility supported by the
results of studies on the progression of pigmented lesions
(127–129, 131, 211, 214, 215, 255, 381). In semiquantitative
study, POMC-derived antigens were below the limit of
detectability by immunocytochemistry in normal skin melanocytes and in benign blue nevi (255). In contrast, common and dysplastic melanocytic nevi showed weak positivity for ␣-MSH, ACTH, and ␤-endorphin antigens in 14,
33, and 44% of the specimens, respectively, with a tendency for higher expression levels in dysplastic nevi
(255). In melanoma, POMC antigens were easily detectable in ⬎50% of cases, and the stain was also more intense
and diffuse in the more aggressive forms: the nodular type
(pure vertical growth phase), the vertical growth phase of
superficial spreading type, acral lentiginous types, and
metastatic melanomas (211, 255). Direct measurement of
␣-MSH with RIA found that concentrations in skin melanomas were variable from 0.21 to 2.32 pmol/g wt and in
lymph node metastasis from 0.31 to 4.25 pmol/g wt (214).
The ␣-MSH-IR detected in melanomas was chromatographically heterogeneous; only a small fraction represented authentic ␣-MSH peptide, whereas most of the
immunoreactivity corresponded to more hydrophobic
species of larger molecular weight (128, 131). The larger
molecular weight ␣-MSH-IR species probably have preserved COOH-terminal amino acid sequence and may contain the whole 1–13 ␣-MSH sequence (128, 131).
Immunocytochemistry studies performed in 30 specimens from basal cell carcinoma patients showed heterogeneous distribution of immunoreactive ␣-MSH, ␤-MSH,
and ACTH peptides in tumor cells, lesional and perilesional areas, epidermal and follicular keratinocytes, dermal mononuclear cells, and extracellular matrix (363).
The frequency of peptide detection was similar in lesional
and perilesional areas and in tumor cells. RP-HPLC studies combined with RIA monitoring of eluted fractions
documented that ACTH and ␣-MSH of lesional and perilesional areas corresponded to the authentic peptides; an
additional peptide eluted at the same time as desacetyl␣-MSH. POMC mRNA was also detected by RT-PCR in
extracts of perilesional and lesional skin (363). Most interestingly, the MC1-R gene encoding the receptor activated by MSH and ACTH was also expressed in the same
lesional and perilesional skin, suggesting paracrine/autocrine mechanisms of action for the peptides. Perhaps
POMC peptides facilitate basal cell carcinoma development and/or progression (363).
Ghanem et al. (127) found that melanoma patients
have increased serum levels of ␣-MSH-IR, and these could
be positively correlated with progression of clinical stage
or level of invasion. This suggests that local tissue MSH
could eventually spill into the blood. The possibility of
995
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SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
342). Of further interest, these endothelial cells express
the convertase PC1, whose mRNA production is again
stimulated by UVA as well as IL-1 and ␣-MSH (341).
2. Modulators of POMC gene expression
in the skin
TABLE
Agent
3. Regulation
Cytokines and growth factors
IL-1
TNF-␣
Endothelin-1
TGF-␤
Physicochemical factors
Ultraviolet radiation
Dibutyryl cAMP
TPA and PMA
L-Dopa
Dexamethasone
POMC Production
(mRNA and/or Peptides)
Stimulated
Stimulated
Stimulated
Inhibited
Stimulated
Stimulated
Stimulated
Stimulated
Inhibited
TPA, 12-O-tetradecanoylphorbol 13-acetate; PMA, phorbol 12-myristate 13-acetate; IL-1, interleukin-1; TNF-␣, tumor necrosis factor-␣;
TGF-␤, transforming growth factor-␤.
central level, could play a more dominant regulatory role
on POMC peptides production in the skin. In this regard,
the proinflammatory cytokine IL-1 has a significant stimulatory/inductory effect on POMC gene expression in resident skin cells and circulating immune cells including
macrophages (27, 32, 33, 57, 219 –221, 337, 445, 446).
Indeed, IL-1 increases production of POMC mRNA and
ACTH, ␣-MSH, and ␤-LPH peptides in cultured normal
and malignant epidermal melanocytes and keratinocytes
(67, 219 –221, 337, 445, 446). In HDMEC, expression of
POMC gene is also stimulated by IL-1 (341, 342). Another
cytokine, TNF-␣, stimulates production of POMC mRNA
in normal dermal fibroblasts (408), whereas transforming
growth factor (TGF)-␤ inhibits it in the same cell system
and in keratinocytes, but not in keloidal fibroblasts (408).
Neither TNF-␣ nor endothelin-1 affects POMC peptide
production in melanocytes and keratinocytes (67). Further confirming the selectivity of cytokine action, the
release of ␣-MSH by transformed human keratinocyte line
is not altered by the cytokines IL-2, IL-6, TGF-␤, and
interferon (IFN)-␥. Thus selected cytokines and growth
factors produced in the skin can act locally, stimulating or
inhibiting POMC gene expression and peptide production
in a cell type-restricted fashion.
In rodent skin, the expression of POMC gene and
production of POMC peptides appear to be regulated by
the same biological clock that controls hair cycle (104,
122, 273, 356, 360, 368, 371). Although the effector messengers of that clock remain the subject of numerous
hypotheses, a pacemaker, local or distant, would generate
the signals that periodically stimulate and inhibit cutaneous POMC gene expression (104, 272, 273, 276, 356, 360,
368, 371, 372, 376). Because the anagen-induced cutaneous POMC gene expression is inhibited by topical application of the synthetic glucocorticoid dexamethasone,
which also terminates hair growth, it is possible that the
dexamethasone-induced attenuation of POMC gene activ-
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It is generally accepted that translation of the POMC
mRNA requires the full-length transcript composed of
three exons, where exon 1 contains the signal peptide (17,
99, 170, 383). In human skin cells, the size of the POMC
transcript is of 1.2 or 1.3 kb, similar to that detected in the
hypothalamus and pituitary (220, 337, 446). In contrast, in
rodent skin, a shorter 0.9-kb form predominates, although
a full-length 1.1-kb transcript is also detected (104, 360,
371). It is not yet clear which of these forms is translated
in rodent skin, since it is possible that the shorter 0.9-kb
POMC could be translatable (85) because of mechanisms
that would allow the translocation of peptides and proteins lacking the signal sequence (197). Cloning of POMC
mRNA fragments from human skin has shown only 86%
homology with the pituitary transcript, with no differences in the region coding for ACTH and ␤-endorphin
(57). This only partial POMC mRNA homology raises the
question of whether additional nonallelic forms of POMC
are expressed in the skin. It must be noted that lower
vertebrates express two forms of POMC gene (12, 402),
whereas in the mouse genome, two nonallelic ␣- and
␤-POMC genes have been identified (425).
Production of the final ACTH, MSH, and endorphin
peptides is a complex multistep process that requires
POMC processing by prohormone convertases (PC1 and
PC2). The PC1 gene is expressed in human keratinocytes,
where it is upregulated by UVB (47, 48), whereas Scholzen
et al. (341) showed that dermal microvascular cells express PC1 mRNA, which is again stimulated by UV, and by
IL-1 and ␣-MSH. Immunocytochemistry studies showed
that the PC1 and PC2 enzymes are expresssed in the
human skin, in epidermal keratinocytes and melanocytes
(438), and in the anal mucosa (159). In the C57BL/6
mouse, the enzymes are expressed in follicular and epidermal keratinocytes and sebaceous gland (230). The
overall processing of POMC in skin cells yields multiple
forms of ACTH, desacetyl-␣-MSH, ␣-MSH, ␤-LPH, and
␤-endorphin (122, 131, 223, 337, 354, 356, 363, 411, 438,
446), but whether similar posttranslational modifications
of intermediates of POMC, as in pituitary and brain, e.g.,
amidation, acetylation, glycosylation, and phosphorylation, would also occur in the skin remains to be defined.
A list of the factors that can stimulate or inhibit
production of POMC peptides in the skin is presented in
Table 2. The lack of cutaneous access to the rich source
of neuroendocrine factors represented by the hypothalamus suggests that control of full expression of the POMC
gene in the skin is probably different from the pituitary. It
is possible that the immune system, also involved at the
Volume 80
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
oxidative stress, cAMP, and PKC all appear to participate
in the regulation of POMC gene expression.
VII. SKIN AS A TARGET FOR
PROOPIOMELANOCORTIN PEPTIDES
A role for POMC peptides in the regulation of skin
pigmentary system is suggested by observations in the
POMC knock-out mice model; surprisingly, these animals
survive to adulthood (450). Lack of POMC gene expression is characterized by the main phenotypic traits of
severe obesity and adrenal insufficiency; also prominent
is a defect in fur pigmentation (450). This pattern is
strikingly similar to the clinical picture of patients with
pituitary POMC gene mutations that generate allelic forms
with defective production of POMC protein (154, 196).
Affected individuals present with red hair pigmentation,
severe early-onset obesity, and adrenal insufficiency.
There is also a large body of clinical information on
POMC peptides excess syndromes that confirm the skin
as a target for POMC-derived peptides (cf. Refs. 101, 113,
137, 141, 171, 201, 202, 204, 220, 221, 244, 282, 283, 352,
376, 384, 397, 412, 445). For example, humans with pathologically increased levels of plasma ACTH (Addison disease) or excessive ACTH production by tumors (Nelson
syndrome) have hyperpigmentation and skin atrophy
(101, 113, 137, 141), while the administration of MSH or
ACTH peptides stimulates melanogenesis (201, 202, 204).
Prolonged administration of synthetic ACTH in humans
induces acne, skin atrophy, hyperpigmentation, and hypertrichosis (101, 113, 137, 141), whereas elevated serum
concentrations of ␣-MSH are associated with skin pigmentation (289). Additional research performed on human and animal models (see sect. VII, A and C) indicates
that also immune, epidermal, adnexal, vascular, and dermal structures represent additional targets for POMC peptides.
A. Melanocortin Receptors
It is known that the phenotypic effects of POMC
peptides are mediated via interaction with cell surface
receptors linked to the G protein (101, 110, 141, 257, 444).
MSH and ACTH activate melanocortin (MC) receptors,
whereas ␤-endorphin acts predominantly on ␮- and ␦-opioid receptors. The expression of MC and endorphin receptors in different skin compartments is listed in Table 3;
the following section discusses the skin MC receptors.
Investigations performed in frog melanophores
showed that ␣-MSH interacts with cell surface receptors
to induce cAMP production and the final phenotypic effect of skin darkening (2, 141, 201, 350). In S91 melanoma
cells, MSH interacts with specific cell surface receptors,
activates adenylyl cyclase activity, and increases intracel-
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ity may be mediated by a direct effect on the cutaneous
clock (104).
A major cutaneous stressor, UVR, can stimulate/induce cutaneous POMC gene expression as shown in human and rodent normal and malignant cultured keratinocytes and melanocytes (48, 64, 67, 71, 96, 220, 221, 337,
446). The response to UVR was found to be dose dependent when assessing ACTH and ␣-MSH production and
secretion in normal and malignant keratinocytes (67, 71,
219 –221, 337, 446) and of ␤-LPH and ␤-endorphin in keratinocytes (446). These effects were accompanied by correspondingly increased POMC mRNA production . A similar UVR-induced stimulation of POMC gene expression,
with increased ACTH and ␣-MSH production and release
to the culture media, was observed in rodent transformed
keratinocytes and melanoma cells (64, 71). Most recently,
UVB and UVA treatment of HDMEC resulted in increased
expression of the POMC gene with increased production
and release of ACTH and ␣-MSH (341, 342). Humans and
horses exposed to sunlight exhibit increases in the circulating levels of ␣-MSH and ACTH (129, 157, 158), and
experimental whole body exposure to UVR increases
␤-LPH and ␤-endorphin serum levels (23, 205). UV-absorbing topical sun blockers abrogate the ␤-LPH response
(23), implicating mediation by a photoreaction. Although
the pituitary gland was postulated as the source of these
humoral responses, the experiments cited suggest a
stress-sensing role for the skin and also support the skin
as an alternate source for circulating neuropeptides.
Because of the significance of its interaction with the
skin, the contribution of UVR to the production of nuclear
signals deserves further examination. Theoretically, UVR
could activate the genome directly or, indirectly via action
on membrane-bound signaling processes, production of
second messengers, or via pathways activated by oxidative stress (cf. Ref. 378). In support of the latter possibility, N-acetyl-cysteine (NAC), a precursor to glutathione
that acts as an intracellular free radical scavenger, abolished the UVR-stimulated POMC peptide production in
human keratinocytes and melanocytes (67). It was then
postulated that NAC may inhibit POMC peptides production through attenuation of the oxidative stress triggered
by UVR (64, 67). The tyrosine phosphorylation inhibitors
tyrphostin and genistein had no effect on basal or UVRstimulated POMC production (67). Exposure to dibutyryl
cAMP had stimulatory effects on basal ␣-MSH and ACTH
production in a number of cell lines, which include transformed (BALB/c) PAM 212 keratinocytes and Cloudman
S91 melanoma cells, PS-1-HGPRT-1 clone, and normal
and transformed human keratinocytes and melanocytes,
suggesting involvement of cAMP-activated pathways in
that process (67, 71). Finally, phorbol 12-myristate 13acetate and TPA enhanced POMC gene expression in
melanocytes and keratinocytes (219, 220, 337, 446), suggesting involvement of PKC-activated pathway(s). Thus
997
998
SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
TABLE
3. Expression of MC and opioid receptors
MC Receptor
Epidermal keratinocytes
Follicular keratinocytes
Epidermal melanocytes
Follicular melanocytes
Dermal nevocytes
Sebocytes
Sweat gland cells
Endothelial cells
Langerhans cells
Monocytes
Macrophages
Lymphocytes
Fibroblasts
Adipocytes
MC1
MC1
MC1, MC2†
MC1
MC1
MC5
MC1, MC5
MC1
MC1
MC1
MC1
MC1
MC1
MC2, MC5
Opioid Receptor
␮-Opiate
␮-Opiate
ND
ND
ND
␮-Opiate
␮-Opiate
Absent
ND
ND
ND
ND
Absent
Absent
receptor
receptor
receptor
receptor
MC, melanocortin; ND, not done. † Detected by RT-PCR.
lular cAMP (cf. Refs. 201, 244, 279). This is followed by
increases in tyrosinase activity and melanin production
(447, 448), stimulation of dendrite formation (cf. Ref.
101), and variable effects on cell proliferation (244, 277,
279, 284, 285, 287). On the basis of these findings, it was
proposed that in rodent melanocytes the phenotypic effects of MSH are mediated by cAMP through activation of
PKA and phosphorylation/dephosphorylation reactions
(92, 101, 141, 161, 193, 244, 257, 277–279, 281, 284, 285,
367, 448). Binding of MSH to the MSH receptor with
subsequent activation of adenylyl cyclase was found dependent on the presence of calcium in the receptor milieu; calcium binding protein (CBP) may partially activate
the receptor even in the absence of the ligand (105).
Activation of PKC by ␣-MSH may also be involved in
stimulation of melanogenesis (51, 271), and some investigators have suggested that MSH receptor signal transduction may be coupled to phospholipase C-activated
production of IP3 and diacylglycerol with subsequent mobilization of intracellular calcium (51). However, studies
on different melanoma models have generated conflicting
results, e.g., in human melanomas ␣-MSH was found indeed to stimulate IP3 production (399), whereas in hamster melanoma, the MSH signal transduction and subsequent phenotypic effect were linked to cAMP without any
evidence of IP3 production (366). A similar discrepancy is
found in adrenal cortex. Some authors observed that
␣-MSH stimulated exclusively cAMP production without
effect on IP3 (162), whereas others showed a concentration-dependent effect. At low concentrations, ␣-MSH
stimulated IP3 production, and at high concentrations, it
instead stimulated cAMP production (177, 178). The latter
investigators further postulated that the steroidogenic action of ␣-MSH, but not ACTH, involved stimulation of PKC
and tyrosine kinases as the result of phospholipase C
activation (179). To further search for second messengers
of MC2 receptor (MC2-R) different from cAMP, ACTH
was modified by the attachement of o-nitrophenylsulfenyl
to a tryptophan residue (NSP-ACTH). NPS-ACTH was
found to rapidly stimulate intracellular calcium mobilization and production of 15-lipoxygenase metabolites of
arachidonic acid in bovine fasciculata-reticularis cells
(451). Therefore, calcium and lipoxygenase metabolites
may act as additional second messengers of ACTH in
bovine adrenal cells, and the ACTH-(11O24) region may
be important in this regulation (451). However, it is still
unclear whether the reported effects reflect the activation
of solely MC2-R or, of other receptors as for example,
MC5 that has high affinity for ACTH and is also expressed
in the adrenal cortex (248, 431). Pharmacological studies
with cloned MC receptors have shown that their signal
transduction is coupled to activation of adenylyl cyclase
(82, 88, 123, 248 –251, 256, 257). Although modest activation of IP3 production by MSH binding to MC3 was reported (88, 257), there is no evidence that cloned MC1 and
MC2 receptors would be coupled to other than cAMP
second messenger generating systems (88).
The postreceptor pathways activated by ␣-MSH binding to the MC5-R in B lymphocytes involve stimulation of
the Janus kinase 2 (JAK2) and signal transducers and
activators of transcription (STAT1) pathways (52), as well
as transmission through the same phosphorylation pathway used by cytokines and growth factors. In cells of
monocytic lineage, ␣-MSH acts on MC1-R through cAMPactivated pathways to suppress the activation of nuclear
transcription factor NF␬B induced by inflammatory
agents (227). Activation of NF␬B may be required for
expression of cytokines and adhesion molecules (229).
Activation of MC1-R in immune cells inhibits NO and
neopterin production as well as prostaglandin synthesis
(209, 312, 390).
MSH receptors have been detected and characterized
in rodent melanoma cells (64, 68 –70, 95, 101, 161, 175,
176, 244, 265, 266, 277–279, 281, 283–285, 351, 352, 358,
364, 366, 434, 435), normal and malignant human melanocytes (1, 93, 101, 119, 120, 130, 161, 164, 257, 352, 401),
keratinocytes (31, 35, 64 – 66, 220, 264, 363), and other
cutaneous cells and extracutaneous tissues including
brain, adrenal gland, gonads, and immune cells (29, 34, 45,
79, 88, 141, 147, 209, 220, 249, 251, 312, 390). In vivo
experiments on mice showed wide distribution of MSH
binding sites, to almost all organs (406). The work of the
pigment biology group at Yale University has been fundamental in the characterization of cell-surface MSH receptors (38, 95, 193, 201, 244, 277–279, 284, 285, 287, 434, 435,
447– 449). In fact, the observation that after binding the
ligand, the MSH receptor is internalized and translocated
to the Golgi region (434) represents the first demonstration of receptor internalization after binding of a peptide
hormone. Ultrastructural and biochemical assays showed
translocation of the MSH-MSH-R complex from the cell
surface to melanosomes and demonstrated the presence
of actual intracellular MSH binding sites (68, 101, 244, 279,
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Cell Type
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
283). MSH receptor expression was cell cycle dependent
and restricted predominantly to G2 phase (435). This G2
phase coupling of increased MSH receptor expression is
associated with increased cellular responsiveness to the
ligand (40, 64, 234, 283, 449). Factors that raise intracellular cAMP levels such as dibutyryl cAMP and cholera
toxin can also upregulate MSH receptor expression (95).
In general, factors increasing intracellular levels of cAMP,
such as MSH and ACTH, upregulate expression of their
own receptors (70, 71, 249, 291, 400). Positive cooperativity of MSH receptors has been documented in mouse
and hamster melanoma cells as well as in immortalized
human keratinocytes (64, 65, 234, 364).
Melanocortin receptors were characterized in crosslinking experiments that identified a membrane-bound
receptor of ⬃45 kDa in a number of melanocytic lines
(101). Cloning of the MC1-R and MC2-R receptors was
also performed with mRNA isolated from melanocytes
(82, 250). Currently, there is a family of MC receptors that
includes five members MC1-R to MC5-R, that share high
sequence homology (cf. Refs. 88, 171, 251). All five genes
belong to the superfamily of seven transmembrane G
protein-coupled receptors (82, 88, 171, 248 –251); these
are 298 –372 amino acids long and have short intracellular
COOH-terminal and short NH2-terminal extracellular domains. MC receptors are coupled to an adenylyl cyclase,
with possible additional coupling in MC3-R to phospholipase C (cf. Refs. 82, 88, 123, 248 –251). The MC receptors
have different pharmacological profiles of activation by
MSH and ACTH peptides (82, 88, 248 –251, 290, 317, 339,
340). In rodents, the receptor for ␣-MSH, MC1-R, has high
affinity for ␣-MSH, low for ACTH and ␤-MSH, and lowest
for ␥-MSH (88, 248, 250, 251, 317). In humans, MC1-R has
equally high affinity for ␣-MSH and ACTH and lower
affinity for ␤-MSH and ␥-MSH (82, 88, 123, 250, 251). The
receptor for ACTH, MC2-R, exhibits absolute specificity
for ACTH (88, 250). MC3-MC5-R show equal affinity for
␣-MSH and ACTH, whereas MC3-R or ␥3-MSH receptor
has high affinity for ␥-MSH (cf. Refs. 88, 123, 248 –251).
MC1 receptors have been detected in skin, brain, and
immune system; MC2-R in adrenal gland, adipose tissue,
and skin; MC3-R in brain, placenta, gut, and thymus;
MC4-R in brain; and MC5-R in brain, adipose tissue, muscles, esophagus, thymus, prostate, skin, and exocrine
glands that include Harderian, lacrimal, and specialized
(preputial) or nonspecialized sebaceous glands (45, 79,
82, 88, 104, 123, 141, 161, 209, 220, 248, 250, 251, 257, 317,
362, 400, 404, 431). The distribution of MC1-R, MC2-R, and
MC5-R in skin is presented in Table 3. The mRNA for
MC1-R and MC2-R have been detected in rodent skin by
Northern blot hybridization (104). MC2-R mRNA was de-
tected by RT-PCR in human skin biopsy specimens of
compound melanocytic nevus and in cultured normal and
malignant melanocytes (362). Of note, in human melanocytes, ACTH appears to be more potent than ␣-MSH in
stimulation of melanogenesis (161).
MC1-R has a prominent role in regulation of mammalian pigmentation (88, 101, 141, 171, 248, 250, 257, 397). In
rodents, MC1-R is encoded by the extension locus (E),
which has four alleles resulting from point mutations (88,
257, 317). These allelic forms differ in their responsiveness to ␣-MSH and may even constitutively activate adenylyl cyclase without interacting with the ligand. Similar
regulatory features have been described in other species
(88, 171, 257). In humans, mutations at the MC1 locus
generate allelic forms of the receptor which differ in
ligand specificity and most importantly in phenotypic effect concerning hair and skin pigmentation (88, 171, 257,
386, 397, 428). It has also been proposed that defective
MC1-R function may be associated with an increased
incidence of melanoma (429).
MC1-R is also a target for other regulatory proteins.
For example, the agouti signaling protein (ASP), which is
expressed in skin, inhibits the binding of ␣-MSH to
MC1-R, with resulting inhibition of MSH-stimulated cAMP
production and melanogenesis (cf. Refs. 88, 171, 251, 257,
397, 401). ASP also acts as antagonists to the other MC
receptors, MC2-R to MC5-R (cf. Refs. 88, 171, 251). ASP
bound to MC1-R can inhibit cAMP-mediated activation
and melanogenesis, independently of exogenously added
␣-MSH (171, 257, 401). Because signal transduction in
MC1-R is coupled to Gs but not Gi protein, ASP could
antagonize auto- or intracrine effects of endogenously
produced MSH or ACTH. Alternatively, binding of ASP to
MC1-R could generate changes in the receptor immediate
environment that would activate other, unrelated receptors.
Agouti-related protein (AGRP), which shares sequence homology with ASP, is a naturally occurring antagonist of MC3 to MC5 receptors that may be involved in
the hypothalamic control of feeding behavior (452). AGRP
probably acts through competitive inhibition of ␣-MSH
binding to MC3 to MC5 receptors and inhibition of ␣-MSHinduced cAMP production (452). Additional antagonists
of MC receptors are dynorphin peptides (313).
2. Regulation of MC-R expression
Several years ago Pawelek et al. (283) proposed that
UVB-induced melanogenesis was mediated through upregulation of the MSH receptor system. This was based on
observations of upregulated expression of functional
MSH receptors by UVB that amplified the melanogenic
effect of exogenous MSH in a dose-dependent manner
both in vivo and in cell culture systems (31, 38, 40, 48, 64,
68, 71, 283, 378). UVB action appeared to involve arrest of
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1. Molecular characterization
of melanocortin receptors
999
1000
SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
B. Opioid Receptors
Most recently expression of ␮-opioid receptors that
bind with high-affinity ␤-endorphin was detected in cultured human epidermal keratinocytes (30). In human
skin, in situ hybridization and immunocytochemistry has
shown that the receptors are localized to keratinocytes of
the epidermis and ORS of the hair follicles and to peripheral epithelial cells of sebaceous glands and secretory
portion of sweat glands (30). The expression of ␮-opiate
receptors was downregulated by both the antagonist naltrexone and the agonist ␤-endorphin (30). Presence of the
related ␨-opioid receptor has been documented in human
and mouse skin (453). Furthermore, ␤-endorphin acts as a
local pain modulator (148).
C. Phenotypic Effects of POMC Peptides
1. Pigmentary system
The stimulatory role of melanocortins on mammalian
pigmentation has been discussed extensively (101, 126,
141, 155, 161, 171, 201, 203, 213, 244, 257, 284, 336, 352,
374). There is a general agreement that the POMC pep-
tides with the most significant melanogenic activity are
ACTH, ␣-MSH, and ␤-MSH; the activity of ␥-MSH is low,
and that of endorphins and CLIP is undetectable (101, 141,
161, 236, 257, 358, 400). Structurally ACTH and MSH
peptides have in common the amino acid sequence -Tyrx-Met-x-His-Phe-Arg-Trp- that contains the tetrapeptide
His-Phe-Arg-Trp critical for melanotropic activity (141,
160). The functional relevance of ␤-MSH in mammals has
been debated, since some considered it an artifact of
␤-LPH proteolytic degradation (343). However, Bertagna
et al. (26) have demonstrated convincingly that ␤-MSH is
a normal product of POMC processing in human nonpituitary tissues. ␤-MSH stimulates melanogenesis in cell
culture and skin pigmentation in humans (202, 400) and
rodents (101, 201, 244, 279, 306). ␥-MSH peptides have low
melanogenic activity in murine and hamster malignant
melanocytes (358) as well as in frog and lizard melanophores (101, 141, 257). Although the overall role of ␥-MSH
peptides in the regulation of mammalian pigmentation
may be small, selected ␥-MSH peptides could still modulate pigmentation indirectly, by modifying the cellular
response to other melanotropins. For example, ␥2-MSH
may potentiate the melanogenic activity of ␣- or ␤-MSH,
whereas ␥3-MSH, acting as a partial agonist on MSH receptors, can largely inhibit the melanogenic activity of ␣or ␤-MSH (358).
A) MELANOGENIC EFFECTS IN CELL CULTURES. Studies on
rodent malignant and normal melanocytes have uncovered the role of MSH receptors in the regulation of melanocyte functions via cAMP-dependent pathways (101,
141, 155, 201, 244, 257, 278 –286, 366). Melanogenesis is a
highly regulated process modified by posttranslational,
translational, or transcriptional mechanisms (101, 141,
244, 257, 279). In melanoma cells, both ␣- and ␤-MSH
stimulate melanogenesis activating tyrosinase as well as
post-dopa oxidase steps (101, 141, 257, 281, 283). In rodent malignant melanocytes, ␣-MSH and ␤-MSH are more
potent than ACTH in stimulation of melanogenesis (101,
244, 279). The effect of MSH on cell proliferation is variable and depends on cellular genotype (101, 161, 244, 257,
277–279, 284, 285, 287, 288, 352). The finding of inhibition
of proliferation in amelanotic cells indicates that this
effect is unrelated to production of toxic intermediates of
melanogenesis (244, 279, 366). MSH stimulates dendrite
production through a pathway independent from that regulating melanogenesis, although cAMP mediated (257,
366, 367). Similar MSH effects, e.g.., stimulation of melanogenesis, dendrite formation, and stimulation of cell
proliferation, are seen in normal cultured mouse melanocytes (141, 155, 257).
In cultured human melanocytes, ␣-MSH, ␤-MSH, and
ACTH at concentrations in the nanomolar range or lower
stimulate melanogenesis, cell proliferation, dendrite formation, and cAMP production (1, 161, 400). In some studies ACTH was more potent than MSH (161), whereas in
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the cell cycle at the G2 phase, when cultured rodent
melanocytes express maximal MSH receptor activity and
responsiveness to MSH (64, 283). UVB stimulates expression of MC1-R in normal and malignant human and rodent
melanocytes and in keratinocytes (38, 64, 68, 71, 119, 120,
378). When the skin is exposed to UVR, thermal, chemical,
or biological insults, it responds with enhanced production of cytokines, growth factors, ACTH, MSH, and intermediates of melanogenesis (365, 378). In normal and malignant melanocytes, many cytokines such as Il-1␣, IL-1␤,
endothelin-1, adult T-cell leukemia-derived factor/thioredoxin (ADF/TRX), INF-␣, INF-␤, INF-␥, dibutyryl cAMP,
and the hormones ␣-MSH, ␤-MSH and ACTH can upregulate expression of the MC-1 gene and of functional cellsurface MSH receptors (31, 64, 67, 70, 71, 95, 119, 120, 175,
176, 400). IL-1 can also stimulate MC-1 receptor expression in normal and malignant human keratinocytes (31,
64) and HDMEC (341, 342). ␣-MSH, ␤-MSH, and ACTH as
well as factors raising intracellular cAMP have similar
effects in transformed keratinocytes (31) and HDMEC
(341, 342). Melanin precursors such as L-tyrosine and
phosphorylated isomers of L-DOPA also stimulate expression of MSH receptors and melanogenic responsiveness
to ␤-MSH (233, 364, 377). Retinoic acid, while stimulating
MSH receptor expression, inhibits MSH-induced melanogenesis (69, 265). In addition, retinoic acid and vitamin E
inhibit MSH-sensitive adenylate cyclase activity in mouse
melanoma cells (328). TNF-␣ inhibits MC1 expression in
melanocytes (119).
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
2. Epidermis
Since the detection of MSH binding sites in cultured
human squamous cell carcinoma and immortalized keratinocytes (31, 65), several groups, with a single exception
(400), have shown that human keratinocytes express both
the MC1-R gene and MSH receptors (35, 47, 48, 64 – 66,
220, 264, 363). Moreover, the MSH receptor protein expressed on the cell surface of keratinocyte is similar to
that characterized in pigment cells (65). Experiments in
HaCaT keratinocytes showed that ␣-MSH stimulates cell
proliferation and downregulates 70-kDa heat shock protein (HSP70) expression (264). ␣-MSH inhibition of HSP70
expression was only observed at high calcium concentrations when keratinocytes were induced to differentiate,
and it was accompanied by increased sensitivity to oxidative stress and decreased survival (264). In agreement
with that finding is the enhanced MC1-R gene expression
associated with calcium-induced epidermal keratinocyte
differentiation (64). Further studies in keratinocytes
showed that ␣-MSH can modulate cytokine production
(47, 48, 220, 314). Specifically, ␣-MSH stimulates production of the immunoinhibitory IL-10 and inhibits the IL-1induced production and secretion of IL-8 and GRO␣. It
has been proposed that ␣-MSH inhibition of IL-1 effects is
mediated by downregulation of NF␬B (219). In human
adult skin, epidermal keratinocytes are negative for
MC1-R antigen, with the exception of perilesional keratinocytes of the skin involved by melanoma (35). In contrast, epidermal keratinocytes in fetal skin are positive for
the MC1-R (35). A role for ACTH on epidermal keratinocyte function is unclear, although clinically ACTH has
been implicated in the pathogenesis of acanthosis nigricans (113, 137).
␥1-, ␥2-, and ␤-MSH at the high concentration of 10⫺6
M stimulate mouse epidermal keratinocyte proliferation
in organ culture of telogen skin, but not in anagen skin
(370, 375). ␤-MSH inhibits epidermal keratinocyte proliferation in anagen IV (370, 375), whereas ␣-MSH shows the
same inhibitory effect on telogen skin (273). ACTH at high
concentrations inhibits DNA synthesis in epidermal keratinocytes (356).
The finding of increased ␤-endorphin levels in sera of
patients with atopic dermatitis and psoriasis (125, 135,
136) has suggested a pathogenic role for the peptide in
those conditions. Actual ␮-opiate receptors, downregulated by ␤-endorphin, have been detected in epidermal
and follicular keratinocytes (30). Also the ␮-opiate receptors antagonist naloxone can relieve itching in patients
with chronic liver diseases, but it is unclear whether the
effect is exerted at the cutaneous or systemic levels (24).
3. Dermis
Human dermal fibroblasts have been recently recognized as a target for ␣-MSH (36, 191). Thus ␣-MSH stimulates synthesis and activity of collagenase/matrix metalloproteinase-1 in a dose-dependent manner (191). ␣-MSH
alone stimulates IL-8 release; however, when added together with IL-1, it inhibits the IL-1-induced IL-8 secretion
from fibroblasts (36). These effects may be mediated by
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other reports both peptides were equipotent (1, 400).
␥-MSH, which stimulates cAMP production, has no significant effect on melanogenesis or proliferation when
added alone at concentrations equal to or lower than 100
nM in human or rodent melanocytes (400). Among the
effects of ␣-MSH and ACTH on melanogenesis are increases in concentration of tyrosinase and tyrosinaserelated proteins (1, 400, 401) and in the eumelanin-topheomelanin ratio (161). ␣-MSH can also stimulate
attachment of human melanocytes to laminin and fibronectin (161) and inhibit TNF-␣-stimulated intercellular
adhesion molecule-1 expression in normal and malignant
human melanocytes (149, 246). Mutations in MC1 receptor that produce unresponsiveness of epidermal melanocytes to MSH have resulted in the red hair phenotype
(257, 428).
B) MELANOGENIC EFFECTS IN VIVO. In rodents, application of
␣-MSH stimulates melanogenesis or switches pheomelanogesis to eumelanogenesis (cf. Refs. 88, 101, 126, 140, 141,
257, 405). In several strains of adult mice as well as in
Siberian hamsters, ␣-MSH specifically stimulates follicular
melanogenesis, depending on genotype and hair cycle (53,
54, 88, 126, 140, 141, 203, 213, 257). For example, e/e mice are
not responsive to MSH propigmentary action (405). ␣-MSH
stimulates tyrosinase activity at the transcriptional, translational, or posttranslational level depending on the phase of
hair cycle (53, 54, 101, 126, 141, 257). This is consistent with
the hair cycle restricted expression of melanogenesisrelated genes, protein concentration, and enzymatic activity (368, 369, 373). ␤-MSH also stimulates tyrosinase
activity, as observed in skin of newborn Syrian golden
hamsters as well as black and brown mice (306), and has
actual melanogenic activity in adult guinea pigs and hairless mice (38, 39). Overall, the promelanogenic effect of
MSH peptides has been documented in a number of species (88, 101, 126, 141, 257).
In humans, the systemic administration of ␣- and
␤-MSH or ACTH stimulates skin pigmentation (202). Subcutaneous application of ␣-MSH enhances tanning in sunexposed areas of the skin (204), whereas the skin and hair
pigmentation of patients with Addison disease or Nelson
syndrome is related to increased concentration of circulating ACTH (101, 113, 137, 257). Furthermore, increased
skin pigmentation has been described in a patient having
increased ␣-MSH hypersecretion without adrenal failure
(289). In most patients with ACTH/␣-MSH excess, hyperpigmentation is generalized but most prominent in sunexposed areas.
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SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
whereas melanocortins such as ␤-MSH and ␥-MSH, which
require the expression of other MC receptors, exhibit less
pronounced immunomodulatory activity. It is not yet
clear whether MC-1R expressing immunocytes are also
affected by agouti protein.
Acting on vascular endothelial cells ␣-MSH directly
stimulates the adherence and transmigration of inflammatory cells, a prerequisite for immune and inflammatory
reactions. This effect could be mediated through the expression of adhesion molecules such as E-selectin and
VCAM (see above). E-selectin is required for the rolling of
cutaneous lymphocyte-associated antigen (CLA)-expressing lymphocytes and VCAM, which mediates lymphocyte
flattening and transmigration, is the ligand for VLA-4 expressed on lymphocytes (133, 156). Therefore, ␣-MSH
could influence the outcome of a local immune response
by shifting the expression of adhesion molecules. However, in ongoing inflammatory reactions characterized by
the upregulation of proinflammatory cytokines, ␣-MSH
seems to function as a downregulatory signal.
An important example of the immunosuppressive capacity of ␣-MSH is demonstrated by its effect on the
outcome of the contact hypersensitivity (CHS) reaction
(Fig. 8). Thus administration of ␣-MSH, systemic or topi-
4. Immune system
The POMC peptides ␤-endorphin, ACTH, and ␣-MSH
have strong immunomodulating potential resulting in an
overall immunosuppressive effect (32, 33, 111, 209, 269,
346). The melanocortin ␣-MSH seems to have the widest
spectrum of immunomodulating capacities. Human and
murine monocytes as well as macrophages express
MC1-R, and LPS and mitogens enhance its expression on
monocytes, whereas several cytokines are without effect
(28, 312, 390). When cultured in the presence of granulocyte-macrophage colony-stimulating factor, IL-4, and
monocyte conditioned medium, human peripheral bloodderived dendritic cells express MC-1R with the highest
levels in the fully mature cells (21, 22). It must also be
noted that whereas POMC peptides affect the function of
T, B, and NK cells, it is not yet clear whether these cells
express any of the known MC receptors. MC1-R is nevertheless expressed on cells of the monocytic lineage and
on cells involved in the modulation of immune and inflammatory responses such as neutrophils, mast cells,
endothelial cells, keratinocytes, and endothelial cells (34,
36, 47, 63, 147, 304). The MC1-R ligands ␣-MSH and ACTH
affect the function of cells involved in immunoregulation,
FIG. 8. ␣-MSH applied topically prevents nickel-induced contact
dermatitis. On day 0, ␣-MSH cream (100 ␮M) (left) or placebo (cream
only) (right) was applied in an occlusive dressing for 2 h. Afterwards, a
patch test with nickel at concentrations 0, 0.01, 0.1, 1, and 5% was
performed. The skin was inspected and photographed 2 days later.
Pretreatment with ␣-MSH inhibited the erythematous response to
nickel.
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its effects on AP-1 and NF␬B function. Thus ␣-MSH directly activates AP-1, but it inhibits IL-1-induced AP-1
activation and stimulates NF␬B, without affecting IL-1induced DNA binding (36). These effects may be mediated
by MC1-R, because this receptor is expressed on skin
fibroblasts (36).
HDMEC also express functional MC1-R as detected
by molecular probing for gene expression, by binding of
125
I-labeled ␣-MSH, and by the stimulation of cAMP production by ␣-MSH (341, 342). ␣-MSH also stimulates in a
dose-dependent manner the production and secretion of
IL-8 and GRO␣, being synergistic with TNF-␣ and IL-1
(342). These effects appear to be dependent on cAMP
production and activation of PKA. Thus ␣-MSH may play
a crucial role on endothelial cell function, decreasing the
adherence and transmigration of inflammatory cells, a
prerequisite for immune and inflammatory reactions.
There is evidence on HDMEC that ␣-MSH, which by itself
upregulates the expression of E-selectin and vascular cell
adhesion molecule (VCAM) mRNA, inhibits the LPS-mediated upregulation of these adhesion molecules (172–
174, 220, 221). These findings were confirmed at the protein level and the functional level by adhesion assays
using T lymphocytes and cultured human dermal microvascular endothelial cells (172, 174). ␣-MSH, although
capable of activating NF-␬B by itself on endothelial cells,
blocks completely the LPS- or IL-1-mediated NF␬B activation (172–174). These findings suggest that ␣-MSH modulates the activity/availability of a transcription factor
required for VCAM and E-selectin activation.
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
would be in allergic diseases such as contact dermatitis
(see Fig. 8), atopic dermatitis, asthma, autoimmune diseases, and organ transplantation. In contrast, cutaneous
tumors may be associated with overproduction of POMC
peptides, which may represent a mechanism for escape
from immune surveillance (127–129, 223, 353, 363, 367). In
these cases, neutralization of ␣-MSH could represent a
useful approach.
In addition to causing skin damage, UVR is associated with cutaneous and systemic immunosuppression
(220, 378). Thus UVR impairs the function of epidermal
immunocompetent cells such as Langerhans cells and
induces the production of immunosuppressing cytokines.
In the preceding sections we reviewed the stimulatory
effect of UVR on the cutaneous production of POMC
peptides and on expression of MC1-R by skin cells. These
data in conjunction with expression of functional MC1-R
on immune cells implicate POMC-MC1-R axis as an important coordinator in the response to UVR. Such effect
addressed probably at attenuating the UVR-induced inflammatory reaction could be exerted directly or indirectly. In the latter, UVR-stimulated ␣-MSH expression
would induce production of immunosuppressive factors,
resulting in local (skin) and systemic immunosuppression
(220, 378).
5. Hair
Hypertrichosis is a process whereby a minute, nonpigmented vellus hair follicle (HF) is converted into a
large terminal HF that produces strong, pigmented hair
shafts. To some extent this process may, at least in part,
reflect a change in HF cycling, since hypertrichotic HF
have a substantially longer anagen phase than the original
vellus HF (cf. Ref. 272). In humans, overproduction of
ACTH, e.g., by pituitary tumors or therapeutic administration of ACTH, is a well-recognized cause of acquired
hypertrichosis (272, 444). This induction of hypertrichosis
by ACTH provides circumstantial evidence that the neuropeptide may stimulate and/or prolong anagen. ␣-MSH
may also have a role in the regulation of hair growth,
since ␣-MSH receptors have been detected in the human
HF (273).
In minks and weasels, the effect of POMC peptides
on hair growth has been the subject of detailed studies
(cf. Refs. 126, 272). Thus it has been observed that hypophysectomy prevents the spontaneous onset of molting, an effect corrected by exogenous ␣-MSH or ACTH
(325, 326). Furthermore, in the mink, bilateral adrenalectomy causes a sharp rise in pituitary ACTH release and
premature onset of anagen (322, 324). In fact, hair growth
in mink can be induced directly by intracutaneous injection of ACTH, but not ␣-MSH (323) (Fig. 9). In the C57BL6
mouse, ACTH has a bimodal hair cycle-dependent effect
on hair growth, e.g., intracutaneous injection of ACTH in
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cal, suppresses CHS at both the elicitation and sensitization phases (138, 153, 209, 315, 349). In addition, when
␣-MSH is applied before epicutaneous sensitization with
haptens, it induces tolerance, which is hapten specific,
since animals can be still sensitized with other antigens.
The induction of hapten-specific tolerance by ␣-MSH may
be mediated by IL-10, because it is blocked by administration of anti-IL-10 antibodies (138). Furthermore, in the
mouse, a single intravenous ␣-MSH injection results in
significant elevation of IL-10 plasma levels lasting for
more than 2 wk (220). Another mechanism involved in
␣-MSH tolerance induction may be its downregulatory
effect on the expression of accessory molecules such as
CD86 and CD40 on antigen-presenting cells (21, 22, 28).
Therefore, ␣-MSH may impair the function of antigen
presenting cells (APC) and shift the outcome of an immune response toward tolerance acting directly as well as
via IL-10 induction. The notion that ␣-MSH interferes with
the function of APC has received support from experiments with Langerhans cells prepared from normal murine skin. The cells were treated in vitro with ␣-MSH
derivatized with dinitrofluorobenzene (DNFB) and then
used to induce CHS in naive syngeneic mice. Treatment
with ␣-MSH impaired Langerhans cell ability to induce
CHS but failed to induce tolerance, suggesting that additional pathways are responsible for antigen tolerance induction (89); thus a second application of the allergen
induces production of proinflammatory cytokine IL-1
which upregulates the expression of adhesion molecules
on endothelial cells. Pretreatment with ␣-MSH before
challenge downregulates the expression of adhesion molecules on endothelial cells (172). Therefore, inflammatory
cells required for the CHS reaction are unable to adhere
and penetrate through the vessel wall, and CHS is suppressed. These findings suggest a therapeutic role for
␣-MSH in cutaneous immune responses.
There is evidence from several studies indicating that
most of the anti-inflammatory effects of ␣-MSH are exerted by its NT tripeptide (209, 210). This tripeptide can
actually compete with ␣-MSH for MC-1R binding and, by
itself, induces IL-10 production by monocytes as well as
downregulates CD86 expression (29). In vivo the NT MSH
tripeptide is capable of blocking the induction as well as
the elicitation of CHS, similar to the intact ␣-MSH molecule. In addition, epicutaneous application of the tripeptide at the site of sensitization suppresses the elicitation
of CHS and induces tolerance (220). Therefore, topical
application of these tripeptides, of ⬃350 Da molecular
mass, and thus capable of penetrating the epidermis, may
represent a novel approach for the treatment of allergic
and inflammatory skin diseases.
␣-MSH as well as its NT tripeptide can apparently
serve as antagonist of proinflammatory signals and
thereby downregulate immune and inflammatory responses. Therefore, its major therapeutical potential
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Volume 80
6. Sebaceous glands
FIG. 9. ACTH induces anagen development in minks. Minks were
injected intradermally with ACTH (A: arrows) or with ␣-MSH (B: arrows). The contralateral hip of each mink was injected with solvent
control (PBS). [From Rose (323), with permission from Blackwell Science, Inc.]
telogen skin induces anagen development (275), whereas
in anagen skin it induces the premature onset of catagen
(228).
The C57BL6 mouse has been also studied as a model
for the effect of POMC peptides on hair growth (228, 273,
275, 356, 370, 371, 375). In mice, hair growth is synchronized along three developmental stages: resting (telogen),
growth (anagen), and regression (catagen) (272, 368). The
anagen follicle produces the hair shaft formed by pigmented, keratinized epithelial cells. Hair growth and the
cyclic activity of the hair follicle are timed by a “biological
clock” of unknown nature through as yet ill-understood
tissue interactions. In rodents, the cyclic activity of hair
follicles is accompanied by periodic changes in the physiology of the entire skin (cf. Refs. 272, 368). These are
expressed morphologically as skin thickening, increased
vascularization, and skin pigmentation. The cyclic activity
of hair is coupled to cyclic changes in local immune
system (272, 273); in the pigmentary system (368, 369,
373); in POMC expression, production of POMC peptides,
ACTH, ␣-MSH, and ␤-LPH influence sebaceous gland
function (412). In the rat, ACTH has sebotropic activity
that has been explained by its stimulation of adrenal
androgens and progesterone secretion, since adrenalectomy completely inhibits this sebotropic effect. Also in
rodents ␣-MSH stimulates sebum secretion and lipogenesis in cutaneous sebaceous glands and in specialized pheromone-producing preputial glands acting as trophic factor for those glands. ␣-MSH action on the preputial glands
of rodents stimulates production and release of female
sex attractant odors and of male aggression-promoting
pheromones (412). ␣-MSH specifically stimulates wax and
sterol ester biosynthesis (79, 412). It has been postulated
that the sebotropic activity of ␣-MSH and ACTH is mediated by a peptide sequence different from the melanotropic one (412). In rodents, ␣-MSH and perhaps ACTH
may be important for skin thermoregulation, preventing
overwetting of hairs, and by behavior regulation through
their action on nonspecialized and specialized sebaceous
glands (412).
MC5-R that are fully functional are actually expressed in cutaneous sebaceous and preputial glands and
in Harderian and lacrimal glands (79, 431). In the latter,
melanocortin binding sites have been detected and ACTH
and ␣-MSH stimulate lacrimal protein production and
peroxidase secretion (79, 431). ACTH also stimulates porphyrins synthesis by Harderian glands (79). MC5-R-deficient mice have severely defective cutaneous water repulsion and thermoregulation, from impaired sebaceous
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and expression of MC1-R (104, 122, 356, 360, 370, 371);
and in hair follicle innervation (276). It has been proposed
that the hair cycle-dependent local production of POMC
and expression of the corresponding receptors are integral effectors of the biological clock that regulates cyclic
activity of hair follicles, skin, and subcutis. In this context
POMC peptides imported from extracutaneous sources
may have limited effects because of competition for local
receptors with endogenous peptides; therefore, any effect(s) of systemic supplies would be restricted to the
phases when local production is low or absent. For example, ␥- and ␤-MSH at pharmacological doses stimulate
DNA synthesis in the epidermal compartment of mouse
skin (370, 375). However, this effect is seen only in telogen but not during anagen development. Furthermore,
pharmacological doses of ␣-MSH inhibit proliferation of
epidermal and follicular keratinocytes, but again only in
telogen and not anagen skin (273). ACTH also acts in
telogen skin, where it has a dose-dependent dual effect,
e.g., at physiological doses it stimulates DNA synthesis in
dermal but not epidermal compartments, whereas at
pharmacological doses ACTH inhibits DNA synthesis in
both dermal and epidermal compartments (356).
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
lipids production (79). In the MC5-R knock-out mice,
Harderian gland function is also impaired (79), suggesting
a role for MC5-R in the protection of the eye from environmental stresses.
In humans, it is likely that MSH and ACTH peptides
act on sebaceous glands functions, since hypopituitarism
is associated with decreased sebum production (137).
VIII. REGULATION OF THE CUTANEOUS
CORTICOTROPIN RELEASING HORMONEPROOPIOMELANOCORTIN SYSTEM
UVR also has a dominant stimulatory role on CRH
and POMC peptide production as well as in the expression of the corresponding receptors amplifying the phenotypic effects of MSH. Thus UVR stimulates CRH peptide production in human melanocytes in a dosedependent manner with increased production at higher
levels of radiation (355). UVR also stimulates POMC gene
expression with enhanced production and secretion of
POMC peptides such as ACTH, ␣-MSH, ␤-LPH, and ␤-endorphin in a number of rodent and human cutaneous cell
systems (48, 64, 67, 71, 96, 219 –221, 337, 341, 342, 446).
Also stimulated by UVR is the expression of prohormone
convertase PC1, responsible for the processing of both
pro-CRH and POMC (341). Recent data suggest that UVRstimulated CRH and POMC peptide production may be
mediated by UVR-triggered oxidative stress (64, 67, 378).
Thus the powerful cutaneous stressor represented by
UVR stimulates all of the components of the regulatory
arm (production of CRH and POMC peptides) in the local
CRH-POMC system. In addition, UVR activates the functional arm of the system by inducing expression of the
corresponding receptors. The latter effect is illustrated by
the stimulation of MC1-R mRNA with increased expression of functional MSH receptors that follows, in a dosedependent manner, UVR exposure (38, 64, 68, 71, 119, 120,
378). The UVR stimulatory effect on functional MSH receptors has been correlated with amplification of the
melanogenic effect of MSH peptides in number of cell
culture systems (31, 38 – 40, 64, 68, 71, 283); it is also seen
in vivo, where it is associated with melanocyte proliferation (38, 39, 378).
B. Cytokines
These secretory products of the skin immune system
(SIS) also regulate cutaneous CRH-POMC system activity.
The cytokine IL-1 has significant stimulatory effects on
POMC gene expression and on the production of POMCderived ACTH, ␣-MSH, and ␤-LPH peptides by resident
skin cells and circulating immune cells (27, 32, 33, 67,
219 –221, 337, 341, 342, 445, 446). There is parallel stimulation of PC1 gene expression (340, 341), and IL-1 also
stimulates MC1-R expression (31, 64, 119, 220, 341, 342).
Another cytokine, TNF-␣, stimulates POMC gene expression in dermal fibroblasts (408); TGF-␤ has the opposite
effect, inhibiting POMC gene expression in the same cell
system and in keratinocytes (408). Other related products
such as endothelin-1, ADF/TRX, INF-␣, INF-␤, and INF-␥
can also stimulate the expression of functional MSH receptors on melanocytes (31, 64, 70, 71, 95, 119, 120, 175,
176, 400). Thus, similar to UVR, the SIS also participates,
through the opposing action of selected cytokines, in the
regulation of local expression of POMC and its corresponding receptors.
C. Hair Cycle
In rodents, this cyclic process is characterized by
dramatic changes in skin physiology, with variations in
CRH content, expression of the POMC gene, production
of POMC peptides, expression of CRH-R1 and MC1-R
receptors, and expression of PC1 and PC2 convertases
(104, 122, 230, 273, 321, 356, 360, 368). Thus the local
pacemaker that determines the hair cycle also determines, directly or indirectly, the expression of the CRHPOMC system in rodent skin (104, 272, 273, 276, 356, 360,
368, 371, 372, 376). The effector messengers regulating
cyclic follicular activity remain to be defined (104, 272,
273, 276, 368, 376).
D. Disease States
In normal corporal human skin (whole body except
scalp and face), expression of the POMC gene is low or
below the level of detectability (214, 381). In contrast,
gene expression becomes readily detectable in pathological conditions such as keloids, psoriasis, basal and squamous cell carcinomas, vitiligo, and melanomas (127, 131,
135, 211, 212, 255, 363, 381). Most interestingly, malignant
progression of pigmented lesions is accompanied by increased expression of POMC peptides in the atypical
melanocytes of dysplastic nevi or melanoma (211, 255,
381). Concordantly, increased production of POMC peptides is found in the more advanced and aggressive forms
of melanoma (127, 128, 131, 250, 353, 367, 457). Thus
disease process can stimulate cutaneous POMC gene expression.
E. Cellular Metabolism Mediators
Factors that raise intracellular cAMP levels such as
dibutyryl cAMP, forskolin, and MSH stimulate production of
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A. UVR
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SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
CRH and of POMC-derived peptides in skin cells (64, 67, 341,
361). In addition, dibutyryl cAMP and the hormones ␣-MSH,
␤-MSH, and ACTH stimulate expression of the functional
cell surface MSH receptors in melanocytes, keratinocytes,
and dermal microvascular endothelial cells (31, 64, 70, 71,
95, 119, 120, 175, 176, 341, 342, 400); in the latter, phorbol
12-myristate 13-acetate and TPA enhance POMC gene expression (219, 220, 337, 446). Together these observations
suggest that PKA and PKC mediate significant regulatory
pathways in cutaneous CRH-POMC system.
F. Glucocorticoids
IX. PHYSIOLOGICAL SIGNIFICANCE OF
CUTANEOUS PRODUCTION OF
CORTICOTROPIN RELEASING HOMRONE
AND PROOPIOMELANOCORTIN
As noted above, local production of CRH and POMC
and corresponding receptors expression can occur in response to environmental stimuli that do not reach the
brain (e.g., UVR). This evidence strongly implies that
cutaneous production of these peptides, and their effect
on skin function may be regulated independently from
their systemic counterpart. The effects of the CRH/POMC
responses are cell-compartment and function specific.
For example, CRH and related peptides stimulate intracellular calcium accumulation in malignant melanocytes
and in normal and malignant keratinocytes and affect cell
proliferation (109, 186 –188, 357, 379). CRH action is nevertheless modified by a timing component, since implantation of slow-releasing CRH capsules in the vicinity of HF
with the telogen phase will effectively arrest hair cycle
progression, producing an extended telogen phase (273).
Overall, peripheral CRH acts as a growth factor for the
epidermis and HF, has antiedema effects, and is a vasodilator agent potentially enhancing blood flow through
dermis acting on the vascular smooth muscle and endothelium (19, 86, 114, 116, 134, 316, 320, 338, 422, 440). CRH
could be important for local hemostasis, since it inhibits
IL-1-induced prostacyclin and prostaglandin synthesis
(114, 116). It is also considered an immunomodulatory
factor (9, 134, 142, 237, 268a, 305, 334, 335, 418, 430, 440),
consistent with its ability to induce mast cell degranulation (409).
With regard to the POMC peptides MSH and ACTH,
these stimulate epidermal and follicular melanogenesis,
melanocyte proliferation, and modify immune and secretory functions of pigment cells (cf. Refs. 64, 101, 126, 141,
149, 161, 202, 220, 365, 374, 376, 445). ACTH, ␤-endorphin,
and especially ␣-MSH are strong immunomodulators exerting an overall immunosuppressive effect (32, 33, 111,
209, 220, 269). For example, ␣-MSH can function as an
antagonist of IL-1 and induce production of immunosuppressive cytokines while suppressing the expression of
accessory molecules on APC (22, 28, 58, 138, 147, 219, 220,
254, 314). Of clinical significance, ␣-MSH and its NH2terminal tripeptide can prevent the induction of the contact hypersensitivity reaction and even block its elicitation (138, 153, 209, 220, 315, 349). ␣-MSH has already been
used successfully for the treatment of contact dermatitis
(Fig. 8). MSH affects epidermal keratinocyte proliferation
stimulating cell differentiation and differentially modulates cytokine production (cf. Refs. 64, 220, 264, 273, 314,
370, 375). ACTH stimulates hair growth by inducing anagen development (Fig. 9) (273, 275, 322, 323). The MC5-R
knock-out mice model, which has defective sebaceous
gland function and thermoregulation (79), provides further evidence for the role of ACTH/MSH in those functions (79, 412, 431). ␣-MSH has a regulatory role in rodent
nonspecialized and specialized sebaceous gland function;
it stimulates lipogenesis and sebum secretion as well as
production and release of female sex attractant odors and
male aggression-promoting pheromones (79, 412, 431).
Finally, MSH stimulates dermal fibroblast collagenase
production and secretion as well as cytokine production
(36, 191, 220). In summary, cutaneous POMC peptides
have marked effects on the pigmentary, immune, epidermal, adnexal, and dermal functions of the skin, enhancing
melanogenesis, stimulating cellular differentiation, stimulating hair growth and sebaceous gland functions, and
attenuating inflammatory reactions.
X. HYPOTHESIS ON AN ORGANIZED SYSTEM
MEDIATING SKIN RESPONSES TO STRESS
A. Hypothesis
The findings in the skin of CRH/CRH-like peptides,
POMC peptides, and their corresponding receptors
strongly advocate against random occurrence (Fig. 10).
Rather, similar to the central levels, expression of these
elements is highly organized. The functional purpose of
this CRH/POMC system would be to respond to external
and internal stresses through local pigmentary, immune,
epidermal, adnexal (HF and sebaceous, eccrine, and
apoccrine glands), and vascular structures to stabilize
skin function and prevent disruption of internal homeostasis. This skin stress response system (SSRS) has
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Dexamethasone inhibits CRH production in cultured
human skin cells and attenuates POMC gene expression
in rodent skin (104, 361). Dexamethasone also inhibits
expression of the MC1-R gene in rodent skin (104), and it
terminates anagen-associated melanogenesis by inducing
catagen (104, 274, 372). Thus, in analogy with their central
action, glucocorticoids attenuate the local CRH/POMC
system activity.
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CRH-POMC SIGNALING IN A CUTANEOUS STRESS RESPONSE
1007
the capacity to regulate its level of expression independent of the CNS. The SSRS operates at the cellular, tissue,
and organ level via a combination of intra-, auto-, and
paracrine mechanisms (Fig. 10). Because of the differences in skin structure between furry animals and humans, as well as the nature of the predominant stress
reaching the viable portion of the skin, the operational
organization of the local CRH-POMC system has characteristic species specificity. In humans, the SSRS is most
reactive to solar radiation and thus linked to the pigmen-
tary system; in rodents (mostly nocturnal animals), the
SSRS is more reactive to chemical insults and coupled to
the activity of adnexal structures.
B. Background to the Organization and Function
of the SSRS
Physiologically, the skin is the body organ with the
most extensive exposure to the environment; as such, it
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FIG. 10. Diagramatic presentation of cutaneous CRH/
POMC system. A: cutaneous sites of CRH and POMC peptide production. B: cutaneous sites of CRH and POMC
receptor expression. C: scheme of CRH/POMC function in
the response to injury, through para- and autocrine mechanisms.
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SLOMINSKI, WORTSMAN, LUGER, PAUS, AND SOLOMON
C. Functional Organization of SSRS
When the normal integrity of the skin is disrupted, it
is most important to restrict maximally the consequent
biological reaction, to preserve its functional properties.
The actions of the CRH-POMC system at the cellular level
prevent spreading of the field of stress. Within this context, the space-restricted paracrine, autocrine, and intracrine mechanisms of action are critical for limiting tissue
damage. Expression of truncated products lacking the
signal peptide that would allow easy export from the cell
would also ensure that the effect would be localized to
structures in the immediate vicinity of manufacturing
sites. The SSRS immunosuppressive activity decreases
recruitment of local immunocytes; local immunoglobulin
and cytokine production would abate, and local dermal
capillary permeability would return to basal levels. Most
important in this conception is the timing of the functional sequence, since CRH-POMC activation must follow
the primary reactive mechanisms. It is possible that the
full expression of CRH-POMC effects may require the
presence of stress-dependent products acting as potential
cofactors. An effect of stress-released molecules acting as
cofactor for CRH-POMC phenotypic effects is supported
by, for example, the finding of pigmentation restricted to
the solar radiation-exposed areas in patients with adrenal
destruction (Addison disease) or with tumoral pituitary
ACTH hypersecretion (Nelson syndrome).
CRH/POMC molecules similar to those produced in
the skin are being released continuously by the HPA axis
and are likely to influence skin function. However, some
degree of cutaneous insensitivity to CRH-POMC peptides
of central origin may result from local impermeability or
in situ degradation of peptides. In contrast, an opposite
endocrine central effect from the low constitutive activity
of the CRH-POMC skin system would seem less likely.
Thus, when the intensity of skin damage is major, by the
time the extent of local involvement might release a large
amount of POMC peptides that could spill into systemic
circulation, the systemic reaction to stress via the central
HPA axis would have been already activated. Therefore,
peripheral contribution to the acute systemic response to
stress would be insignificant. Nevertheless, we cannot
exclude the possibility that in this setting, as well as in
pathological conditions resulting in chronic, sustained
CRH/POMC skin overproduction, the same molecules
could serve a different role as messengers of cutaneous
distress. The latter function might be accomplished directly by the hormonal products themselves, or indirectly
by stimulating ascending neural pathways.
We thank Drs. Z. Abdel-Malek, T. Kishimoto, E. Linton, J.
Pawelek, J. Roberts, and E. Wei for their valuable comments.
The excellent secretarial work of T. Hermann is acknowledged.
This work was supported by National Science Foundation
Grants IBN-9896030, IBN-9604364, and IBN-9405242; American
Cancer Society, IL Division, Grant gg-51; Bane Charitable Trust
Grant LU#9178 (to A. Slominski); Deutsche Forschungsgeimeinschaft Grant Pa 345/6 –1 (to R. Paus); a grant from Wella, Darmstadt (to R. Paus); and a grant from Deutsche Forschungsgeimeinschaft (to T. Luger).
Address for reprint requests and other correspondence: A.
Slominski, Dept. of Pathology, Univ. of Tennessee Memphis,
Rm. 576 BMH-Main, 899 Madison Ave., Memphis, TN 38163.
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