Download The thyrotropin-releasing hormone (TRH)–immune system

Pharmacology & Therapeutics 121 (2009) 20–28
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Pharmacology & Therapeutics
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h a r m t h e r a
The thyrotropin-releasing hormone (TRH)–immune system homeostatic hypothesis
J. Kamath a,⁎, G.G. Yarbrough b, A.J. Prange Jr. c, A. Winokur a
a
b
c
University of Connecticut Health Center, Department of Psychiatry, 263 Farmington Avenue, Farmington, CT 06030, United States
TRH Therapeutics LLC, 2366 NW Pettygrove Street, Portland, OR 97210, United States
University of North Carolina, Department of Psychiatry, 6503 Meadow View Road, Hillsborough, NC 27278, United States
a r t i c l e
i n f o
Keywords:
TRH
Thyrotropin-releasing hormone
Immune
cytokine
Inflammation
Homeostasis
Abbreviations:
CNS, central nervous system
CRH, corticotropin-releasing hormone
D2, type 2 deiodinase
DMV, dorsal motor nucleus of the vagus
HPA, hypothalamic-pituitary–adrenocortical
HPT, hypothalamic-pituitary–thyroid
IEL, intraepithelial lymphocytes
IFN-γ, interferon gamma
IL-1, interleukin-1
IL-2, interleukin-2
IL-6, interleukin-6
LPS, lipopolysaccharide
NTS, nucleus tractus solitarius
PBMC, peripheral blood mononuclear cells
PRL, prolactin
PVN, paraventricular nuclei
SRBC, sheep red blood cells
TNF-α, tumor necrosis factor-alpha
TRH, thyrotropin-releasing hormone
TRH-R, TRH receptor
TSH, thyroid stimulating hormone
VLM, ventrolateral medulla
a b s t r a c t
Decades of research have established that the biological functions of thyrotropin-releasing hormone (TRH) extend
far beyond its role as a regulator of the hypothalamic-pituitary–thyroid axis. Gary et al. [Gary, K.A., Sevarino, K.A.,
Yarbrough, G.G., Prange, A.J. Jr., Winokur, A. (2003). The thyrotropin-releasing hormone (TRH) hypothesis of
homeostatic regulation: implications for TRH-based therapeutics. J Pharmacol Exp Ther 305(2):410–416.] and
Yarbrough et al. [Yarbrough, G.G., Kamath, J., Winokur, A., Prange, A.J. Jr. (2007). Thyrotropin-releasing hormone
(TRH) in the neuroaxis: therapeutic effects reflect physiological functions and molecular actions. Med Hypotheses
69(6):1249–1256.] provided a functional framework, predicated on its global homeostatic influences, to
conceptualize the numerous interactions of TRH with the central nervous system (CNS) and endocrine system.
Herein, we profer a similar analysis to interactions of TRH with the immune system.
Autocrine/paracrine cellular signaling motifs of TRH and TRH receptors are expressed in several tissues and organs
of the immune system. Consistent with this functional distribution, in vitro and in vivo evidence suggests a critical
role for TRH during the developmental stages of the immune system as well as its numerous interactions with the
fully developed immune system. Considerable evidence supports a pivotal role for TRH in the pathophysiology of
the inflammatory process with specific relevance to the “cytokine-induced sickness behavior” paradigm. These
findings, combined with a number of documented clinical actions of TRH strongly support a potential utility of
TRH-based therapeutics in select inflammatory disorders.
Similar to its global role in behavioral and energy homeostasis a homeostatic role for TRH in its interactions with
the immune system is consonant with the large body of available data. Recent advances in the field of
immunology provide a significant opportunity for investigation of the TRH-immune system homeostatic
hypothesis. Moreover, this hypothesis may provide a foundation for the development of TRH-based therapeutics
for certain medical and psychiatric disorders involving immune dysfunction.
© 2008 Elsevier Inc. All rights reserved.
Contents
1.
2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The expression of thyrotropin-releasing hormone and thyrotropin-releasing hormone-receptor in the immune
system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
In vitro evidence for interactions between thyrotropin-releasing hormone and the immune system . . . . . .
In vivo evidence for interactions between thyrotropin-releasing hormone and the immune system . . . . . .
4.1.
Effects of thyrotropin-releasing hormone on the immune system. . . . . . . . . . . . . . . . . . .
4.2.
Effects of cytokines on thyrotropin-releasing hormone systems . . . . . . . . . . . . . . . . . . .
4.3.
Role for thyrotropin-releasing hormone in the regulation of immune responses. . . . . . . . . . . .
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⁎ Corresponding author. University of Connecticut Health Center, University of Connecticut School of Medicine, Department of Psychiatry, 10 Talcott Notch Road, East Lobby, 3rd
Floor, Farmington CT 06030-6415, United States. Tel.: 860 679 6727; fax: 860 679 6781.
E-mail address: [email protected] (J. Kamath).
0163-7258/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.pharmthera.2008.09.004
J. Kamath et al. / Pharmacology & Therapeutics 121 (2009) 20–28
5.
Connections between thyrotropin-releasing hormone and the immune system . . . . . . . . . . . . .
5.1.
Anatomical framework for thyrotropin-releasing hormone–immune system interactions . . . . .
5.2.
Experimental evidence for vagus-dependent thyrotropin-releasing hormone–immune system
interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.
Experimental evidence for vagus-independent thyrotropin-releasing hormone–immune system
interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.
Role of thyrotropin-releasing hormone in the pathophysiology of the inflammatory process. . . .
6.
Thyrotropin-releasing hormone-based therapeutics in inflammatory disorders . . . . . . . . . . . . .
6.1.
Cytokine-induced sickness syndrome as a therapeutic target in inflammatory disorders . . . . . .
6.2.
Challenges and advances in the development of thyrotropin-releasing hormone-based therapeutics
7.
Future investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Ader first used the term “psychoneuroimmunology” in 1980
(Ader, 1980) to describe the increasing body of evidence about
interactions between the brain and the immune system. Since then
research has demonstrated significant involvement of the endocrine
system in brain-immune interactions in both health and disease
states. These multi-directional interactions can occur at many stages
of development, and they are a continual part of the drive to
maintain homeostasis. Defects or deficiencies in one or more of these
systems can lead to a specific disorder or aggravate a variety of other
disorders.
Interactions between the central nervous system (CNS), the endocrine system and the immune system are mediated at multiple
levels. These mediators include secreted chemical messengers such as
hormones, cytokines, neurotransmitters and neuropeptides acting
directly or via the nervous system. Evidence indicates interactions at
the level of receptors (e.g., the presence of neuroendocrine peptide
receptors on immune cells), at the level of secretory function (e.g., the
synthesis and secretion of neuroendocrine peptides by immune cells),
and at the level of signal transduction.
Interactions of specific endocrine systems (e.g., the hypothalamicpituitary–adrenocortical [HPA] axis) with the CNS and the immune
system have been extensively described (Sternberg, 1995; Eskandari &
Sternberg, 2002). Hypophysectomized rats and mice exhibit decreased antibody response, decreased lymphocyte proliferation, reduced
spleen natural killer cell activity, and prolongation of graft survival
(Keller et al., 1988; Nagy & Berczi, 1978). Despite the increasing evidence in individual reports, few reviews have attempted to formulate
interactions between the hypothalamic-pituitary–thyroid (HPT) axis,
the CNS and the immune system (Pawlikowski et al., 1994; Kruger,
1996). To date, no review has delineated the interactions of one of the
critical hormones of the HPT axis, thyrotropin-releasing hormone
(TRH), with immune and other systems. In the present report, we first
review and discuss some of the pivotal evidence for interactions between TRH, the CNS and the immune system and then propose a
functional framework in which to conceptualize the accumulating
evidence. We propose a TRH-immune system homeostatic hypothesis.
The TRH-immune system homeostatic hypothesis states that TRHmediated mechanisms respond to many elements of the immune
system and affect them in ways that tend to maintain or restore
homeostasis.
Finally, we describe potential implications of this framework for
the pathophysiology of certain disorders and provide a rationale for
TRH-based therapeutics.
The tripeptide thyrotropin-releasing hormone (TRH) is known to
control the synthesis and secretion of pituitary thyrotropin (thyroid
stimulating hormone, TSH) and prolactin (PRL) (comprehensive review in Nillni & Sevarino, 1999). TRH-secreting neurons are located in
the medial portions of the paraventricular nuclei (PVN) of the hypothalamus; their axons terminate in the medial portion of the external
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layer of the median eminence (Guillemin, 1978). Originally discovered
in the hypothalamus, consistent with its classical role as a hypothalamic hypophysiotrophic factor, TRH is now known to be distributed
extensively in extrahypothalamic brain structures (Winokur & Utiger,
1974; Yarbrough, 1979) and in other organs and tissues (Lechan, 1993).
Similarly, receptors for TRH are found throughout the central and
peripheral nervous system as well as in other organs and tissues (Sun
et al., 2003). The widespread distribution of TRH and its receptors
suggests other important functions for this tripeptide, including possible critical interactions with other biological systems (Gary et al.,
2003; Yarbrough et al., 2007). The TRH receptors (TRH-R) belong to the
seven transmembrane-spanning, G protein-coupled membrane receptor family (Sun et al., 2003). Two receptor isoforms, TRH receptor R1
(TRH-R1) and TRH receptor R2 (TRH-R2) have been identified (Gershengorn & Osman, 1996). In the brainstem, TRH-R1 has been shown to
be present in the dorsal motor nucleus of the vagus (DMV) and the
nucleus tractus solitarius (NTS), while TRH-R2 has been localized to the
reticular formation, dorsal tegmental nucleus and spinal trigeminal
nucleus (Heuer et al., 2000). TRH signaling occurs mainly via the
phosphatidylinositol–calcium–protein kinase C transduction pathway,
with subsequent elevations in intracellular calcium, and modulation
of K+ channel conductance (Gershengorn & Osman, 1996). Notably,
increasing evidence (Mellado et al., 1999; Montagne et al., 1999; Matre
et al., 2003) supports the distribution of TRH and TRH receptors in the
immune system and a number of studies provide data supporting
potential interactions of TRH with the immune system, even at the
level of regulation of transcription.
2. The expression of thyrotropin-releasing hormone
and thyrotropin-releasing hormone-receptor in the immune system
In addition to its classical function as a hypothalamic hypophysiotrophic factor, the widespread distribution of TRH and its receptors
suggests that the tripeptide plays important roles in other systems.
TRH has been identified throughout the CNS, including retina and
spinal cord (Martino et al., 1980; Gary et al., 2003). TRH immunoreactivity has been detected in several peripheral tissues. Polymerase
chain reaction (PCR) amplification analyses detected the expression
of TRH in testes, adrenal glands, lymphoid organs, thymus, and spleen
(Montagne et al., 1999). Immunohistochemistry analyses of rat adrenal gland extracts showed that TRH identified in this tissue is
synthesized in mast cells (Montagne et al., 1997). It is possible that
TRH identified in other peripheral tissues may, in fact, be synthesized
there in the cells of the immune system. Similar to the expression of
TRH, the expression of TRH receptors has been detected in several
extrahypothalamic brain structures and peripheral tissues (Sun et al.,
2003). TRH receptors have been detected in hematopoietic tissues
related to the immune system, including thymus, bone marrow and
lymphoid tissue (Sun et al., 2003). Northern blot analyses have identified TRH-R mRNA in immune cells (Raiden et al., 1995). Western blot
analyses of extracts of rat lymphoid organs showed expression of TRH-
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R in thymus, mesenteric lymph nodes and spleen extracts (Mellado
et al., 1999; Montagne et al., 1999). Expression analyses of rat tissues
using monoclonal anti-TRH specific receptor antibodies have detected
the presence of TRH receptors in several peripheral tissues related
to the immune system, including thymus and lymphoid tissues
(Fukusumi et al., 1995; Wang et al., 1997; Mellado et al., 1999; Bilek,
2000; Yamada et al., 2000). Analysis of human peripheral blood with
these monoclonal antibodies detected TRH receptor expression in
non-activated and phytohemagglutinin-activated T and B lymphocytes (Mallado et al., 1999). TRH receptor expression has been detected
in both peripheral blood mononuclear cells (PBMC)-derived and in
tonsil-derived B and T cells (Mallado et al., 1999). Altogether, it appears
that TRH and its receptors exist and function as autocrine/paracrine
systems in the immune system and other peripheral tissues and
organs, perhaps analogous to its extrahypothalamic neurotransmitter/
neuromodulatory networks in the CNS.
TRH may also influence the immune network indirectly. The
tripeptide stimulates TSH (and thyroid hormones) and PRL, and both
TSH and PRL have robust immunomodulatory properties (Kelley et al.,
2007). Many different cells of the immune network have been shown to
produce TSH. These include T cells, B cells, splenic dendritic cells, bone
marrow hematopoietic cells, intestinal epithelial cells and lymphocytes
(Klein, 2006). TRH was reported to stimulate the release of TSH from
immune cells, and this effect was completely blocked by triiodothyronine (T3) administration (Komorowski et al., 1993). The presence of
TSH receptors has been documented on multiple cells of the immune
system, including lymphoid and myeloid cells, on select immune cell
populations in the bone marrow, and on intestinal T cells (Klein, 2003).
Similarly, expression of PRL has been shown in many different types of
immune cells, and PRL can be produced by T lymphocytes and other cells
of the immune system (Ben-Jonathan et al., 1996). Detailed discussions
of interactions of TSH, thyroid hormones, and PRL with the immune
system have been provided by Klein (2006) and Yu-Lee (2002).
3. In vitro evidence for interactions between
thyrotropin-releasing hormone and the immune system
Several studies have investigated the role of TRH within the immune
system. Lesnikov et al. (1992) reported that a stereotactic lesion of the
anterior hypothalamic area in mice produced rapid involution of the
thymus and a reduction of lymphocytes in peripheral blood. This effect
was prevented by the post-operational administration of TRH or
melatonin and seemed to reflect direct activity of TRH on thymic targets
or binding sites on lymphocytes. Consistent with this evidence, TRH has
been reported to increase thymocyte cell proliferation in rats (Pawlikowski et al., 1992; Winczyk & Pawlikowski, 2000) and has been shown
to antagonize the involution of the thymus produced by prednisolone
(Pierpaoli & Yi, 1990). Thymectomy in pubertal rats resulted in significant depression of both TRH and TSH concentrations (Serebrov et al.,
1992). TRH receptors have been detected on rat splenocytes (Raiden
et al., 1995), and TRH has been shown to stimulate splenocyte proliferation (Raiden et al., 1995). Conversely, Kunert-Radek et al. (1991)
reported suppression of spontaneous splenocyte proliferation by TRH.
Studies in athymic mice indicate that TRH and TSH significantly influence the development of lymphoid cells associated with intestinal
intraepithelial lymphocytes (IEL) (Wang & Klein, 1995). TRH receptors
have been detected on IEL, and these receptors have been reported to be
involved in the synthesis and secretion of TSH from intestinal T cells
(Wang et al., 1997). Mice with congenitally mutant TSH receptors have
been found to have a selectively impaired intestinal T cell repertoire
(Wang et al., 1997).
In vitro studies of effects of TRH on immune system function have
suggested both stimulatory and inhibitory effects (Pawlikowski et al.,
1994). For example, at low concentrations, TRH enhanced the T cellindependent antigen-induced antibody response via the production of
TSH (Kruger et al., 1989). In contrast, Hart et al. (1990) demonstrated a
decrease in IgG production and inhibition of monocytes by TRH.
Moreover, Grasso et al. (1998) reported a stimulatory effect of TRH on
in vitro interferon gamma (IFN-γ) production by human PBMCs. In
contrast, human whole blood cells stimulated by mitogen, when incubated with TRH and imipramine, showed suppression of IFN-γ and
interleukin-10 (IL-10) production (Kubera et al., 2000). Matre et al.
(2003) established a novel functional link between TRH and the
immune system by providing evidence that the human TRH-R1 receptor is transcriptionally regulated by the hematopoietic transcription factor c-Myb.
In summary, TRH interacts with the immune system both during its
development and in its fully developed state. These interactions are bidirectional and occur at all levels of the HPT axis. The effects of TRH on
the immune system can be either stimulatory or inhibitory and are statedependent. It is important to note that these interactions have been
investigated, to date, in the normal or inflammatory state; they have not
been evaluated in the immunosuppressed state. The emergence of
evidence suggesting interactions of these systems at the level of
transcriptional regulation/signal transduction provides an opportunity
to identify novel links as well as potential therapeutic targets.
4. In vivo evidence for interactions between
thyrotropin-releasing hormone and the immune system
Similar to the in vitro evidence, the in vivo evidence suggests both
stimulatory and inhibitory interactions between TRH and the immune
system.
4.1. Effects of thyrotropin-releasing hormone on the immune system
Consistent with the in vitro evidence, intravenous TRH showed
stimulatory effects on IFN-γ production in five normoprolactinemic
women (Grasso et al., 1998). In healthy controls, intravenous TRH led
to an increase in interleukin-2 (IL-2) concentrations (Komorowski
et al., 1994; Trejbal et al., 2001), while in patients with hypothyroidism
(with high baseline IL-2 concentrations), intravenous TRH caused a
decrease in IL-2 concentrations (Trejbal et al., 2001).
Studies conducted in animal models as well as in humans have
suggested a role for TRH interactions in the pathophysiology of specific
disorders involving changes in the immune system. Preliminary results
have suggested a therapeutic potential for TRH analogs in the
treatment of these disorders. TRH exerted a powerful protective effect
in mice challenged with encephalomyelitis virus (Pierpaoli & Yi, 1990).
It decreased the intensity of fungal invasion, decreased mortality
rate, and increased survival time in a mouse model of experimental
candidosis (Błaszkowska et al., 2004). Shimanko et al. (1992) reported
protective effects of TRH in the treatment of edematous and destructive forms of acute pancreatitis. Intravenous and intra-lymphatic
vessel administration of TRH in 15 patients with acute pancreatitis led
to decreased edema and decreased amylasemia (Shimanko et al.,1992).
In a series of experiments in rats, Yoneda et al. (2003, 2005a) reported
stimulation of hepatic and pancreatic blood flow with microinjections
of a TRH analog in the dorsal vagal complex. The stimulatory effect on
hepatic blood flow was completely blocked by left cervical and hepatic
branch vagotomy but not by right cervical vagotomy (Yoneda et al.,
2003). Similarly stimulation of pancreatic blood flow was blocked by
cervical vagotomy on the side of microinjection but not on the opposite
side or by subdiaphragamtic vagotomy (Yoneda et al., 2005a). The
effect was also blocked by pretreatment with atropine or N(G)-nitro-Larginine-methyl-ester (L-NAME), suggesting involvement of vagalcholinergic and nitric oxide-dependent pathways (Yoneda et al.,
2005a). The same group reported protective effects of a centrally
administered TRH analog on cerulin-induced acute pancreatitis in rats
and blocking of this protective effect by subdiaphragmatic vagotomy or
by pretreatment with L-NAME (Yoneda et al., 2005b). Taché et al.
(2006) reported similar effects of central TRH administration on gastric
J. Kamath et al. / Pharmacology & Therapeutics 121 (2009) 20–28
function. TRH injected into the DMN or cisterna magna increased vagal
efferent discharge, activated cholinergic neurons in gastric submucosal
and myenteric plexuses and induced a vagal-dependent, atropinesensitive stimulation of gastric secretory and motor functions. TRH
antibody or TRH-R1 oligodeoxynucleotide antisense pretreatment in
the DMN or cisterna magna completely abolished this effect (Taché
et al., 2006). A TRH analogue was shown to induce gastric hyperemia
via degranulation of mast cells (Kawakubo et al., 2005; Santos et al.,
1996). Central TRH administration was shown to induce acute gastric
lesions via vagal stimulation of ulcerogenic factors (acid, pepsin,
motility, histamine) (Taché & Yoneda, 1993; Stephens et al., 1988). In
the same set of experiments TRH was shown to have a cytoprotective
effect against ethanol-induced gastric lesions by vagal-cholinergic
stimulation of protective factors (prostaglandin, increased blood flow)
(Taché & Yoneda, 1993).
4.2. Effects of cytokines on thyrotropin-releasing hormone systems
The immune system, mainly involving cytokines, similarly seems to
exert stimulatory or inhibitory effects on TRH systems. Prepro-TRH
mRNA levels did not change in the acute phase of the lipopolysaccharide (LPS)-induced model of inflammation (Boelen et al., 2004). However, a significant increase in the expression of type 2 deiodinase (D2)
mRNA was seen in the hypothalamus. The authors suggested that this
enhanced D2 activity is a precursor for decreased hypothalamic TRH
via increased local T3 generation due to negative feedback. This was
confirmed in subsequent experiments conducted by Boelen et al.
(2006) and by Pekary et al. (2007). Prepro-TRH mRNA concentrations
significantly decreased 48 h after LPS administration in the PVN, and
this correlated with increased expression of the pro-inflammatory
cytokine interleukin-1 beta (IL-1β) in the hypothalamus (Boelen et al.,
2006; Pekary et al., 2007). Boelen et al. (2006) noted that the D2 promoter region contains multiple nuclear factor (NF-kB) binding sites,
suggesting a novel interaction at the level of transcriptional regulation
between the immune system and TRH in the hypothalamus.
Multiple pro-inflammatory cytokines have been tested for their effects
on the HPT axis. Notably, these cytokines affect the HPT axis at multiple
levels, leading to decreases in TRH expression, plasma TSH and thyroid
hormone concentrations. However, the most dramatic effect seems to be
on hypothalamic TRH expression. Continuous intraperitoneal infusion of
interleukin-1 (IL-1) led to a 73% decrease in hypothalamic pro-TRH mRNA
concentrations (van Haasteren et al., 1994). Similarly, a single intravenous
injection of tumor necrosis factor-alpha (TNF-α; cachectin) reduced
hypothalamic TRH (Pang et al.,1989), and increasing daily doses of TNF led
to further significant reduction in hypothalamic TRH concentrations (Pang
et al., 1989). IL-6 has been shown to inhibit TRH-stimulated PRL secretion
and has also been shown to inhibit TRH-stimulated free cytosolic calcium
increase (Schettini et al., 1991).
In summary, the in vivo evidence, like the in vitro evidence,
demonstrates bi-directional interactions between TRH and the immune
system, occurring at all levels of the HPT axis. Evidence supports the
notion that these interactions (stimulatory vs. inhibitory) may be statedependent, suggesting a homeostatic role for TRH in these interactions.
However, just as with the in vitro evidence, effects of cytokines on
TRH and on the HPT axis have been evaluated only in the normal or
inflammatory state. A homeostatic role of TRH in these interactions can
be conclusively established only after evaluations in the immunosuppressed state.
4.3. Role for thyrotropin-releasing
hormone in the regulation of immune responses
In contrast to the LPS model of nonspecific inflammation (T-cell
independent response), where an immediate suppression of TRH is
seen, the T-cell dependent antigens, i.e. sheep red blood cells (SRBC),
elicited a rapid increase in hypothalamic TRH and pituitary TRH-R
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mRNAs in the early phase (4–24 h post immunization). Notably, a
decrease in levels similar to the LPS-induced, i.e. T-cell independent,
response followed this initial rise (Perez et al., 1999). The initial
increase in TRH was accompanied by a rise in plasma PRL levels.
Intracerebroventricular injection of antisense oligonucleotide complementary to rat TRH mRNA resulted in a significant inhibition of
specific antibody production and concomitant inability to produce the
peak in plasma PRL levels in this model. This suggests that the T celldependent immune response and clonal expansion of T cells for
appropriate antibody generation is critically dependent on the early
activation of TRH (Perez et al., 1999). It is unclear which pathways
mediate this early rise in hypothalamic TRH seen in the T-cell dependent
response. It is possible that other neuromodulators (e.g., NPY, CART,
glutamate, and vasopressin), which are activated during this immune
response, may play roles in this early rise in TRH (Wittman, 2008).
Evidence suggests that this early increase in TRH is then overridden by
the direct suppressive effects of proinflammatory cytokines on TRH in
the PVN, as in the LPS model. In summary, evidence also supports a
critical role of TRH in the T-cell dependent immune response. Further
exploration in this arena may lead to other therapeutic applications.
5. Connections between
thyrotropin-releasing hormone and the immune system
The delineation of two paradigms pertaining to interactions between
the CNS, the immune system and the endocrine system has significantly
advanced the field of psychoimmunology. One of these paradigms
pertains to interactions between these systems in the LPS-induced
sickness response. The second paradigm involves interactions between
these systems to control gastric function and control of other visceral
organs. We have already reviewed some evidence for a potential role for
TRH in both of these paradigms. To avoid repetition, we will now review
only the most critical in vivo evidence. We first describe the dynamic
interactions between the CNS, the immune system and the endocrine
system, and then elucidate a potential role for TRH in these interactions
based on the evidence presented. Finally, we establish a foundation for
TRH-based therapeutics in specific illnesses.
Gary et al. (2003) were the first to provide an anatomical and
functional framework to conceptualize diverse TRH pathways and
TRH-mediated physiological and behavioral effects. The four distinct
yet functionally integrated systems described by Gary et al. (2003) and
Yarbrough et al. (2007) provided a framework for the authors to
propose a pivotal role for TRH in the regulation of CNS homeostasis. In
the current section, we delineate a role for TRH in a set of interactions
that integrate the immune system with the CNS and the endocrine
system. On the basis of the evidence provided, we propose that some
of the physiological and behavioral events observed in disorders of
immune function are mediated by effects exerted on TRH systems.
5.1. Anatomical framework for
thyrotropin-releasing hormone–immune system interactions
Current evidence suggests that the hypothalamus and brainstem
serve as the epicenters of immune system interactions with other
systems (Pavlov & Tracey, 2004). These two epicenters also serve to
integrate overall brain responses to immune-derived signals from the
periphery. This integration is achieved via multiple, mainly catecholaminergic, projections from these epicenters to the forebrain and other
brain regions (Gaykema et al., 2007; Pavlov & Tracey, 2004). The critical
areas within these epicenters that are involved in these interactions
include: the PVN in hypothalamus and the NTS, the ventrolateral
medulla (VLM) and the dorsal motor nucleus of vagus (DMN) in the
brainstem. The PVN receives significant, mainly catecholaminergic,
input from the lower brainstem centers (i.e., NTS, VLM and DMN)
(Sawchenko et al., 2000). Select neuromodulators (e.g., corticotropinreleasing hormone [CRH], neuropeptide Y, histamine, and leptin) also
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Fig. 1. Overview of documented TRH and immune system interactions.
play important roles in the pathophysiology of LPS-induced sickness
syndrome. For example, significant increases in CRH in the PVN are
observed after LPS administration.
TRH and TRH receptors have a strong presence in both the hypothalamic and brainstem centers. Neurons in the dorsal vagal complex,
including the DMN, express TRH receptors and are innervated by TRH
fibers originating from TRH synthesizing neurons localized exclusively in
the brainstem nuclei (Bayliss et al., 1994; Lynn et al., 1991). These brainstem nuclei, which contain TRH synthesizing neurons, namely the raphe
pallidus, raphe obscurus, and parapyramidal regions, also harbor vagal
and sympathetic preganglionic motor neurons involved in thermal, cardiovascular, gastrointestinal, and pancreatic regulation (Wittman, 2008;
Taché et al., 2006).
5.2. Experimental evidence for vagus-dependent
thyrotropin-releasing hormone–immune system interactions
As described earlier, TRH administration in specific brainstem areas
has been shown to impact functions of several visceral organs via vagal
afferent-efferent pathways. Morrow et al. (1995) showed that a TRH
analog (RX-77368) administered in the DVC induced gastric contractility.
Microinjection of IL-1 beta (IL-1β) in the DVC (along with RX-77368)
completely blocked this effect. Intracisternal injection of an IL-1 receptor
antagonist abolished the inhibitory effect of IL-1β on the TRH analoginduced gastric contractility (Morrow et al., 1995). Hermann and Rogers
(1995) showed a similar inhibitory effect of another pro-inflammatory
cytokine, TNF-α, on TRH stimulated gastric motility. Compared to the IL1β inhibitory effect (30–120 min postinjection), the TNF-α effect was both
immediate (within 30 s) and longer lasting. The TNF-α inhibitory effect
was dose-dependent and required an intact vagal pathway (Hermann &
Rogers, 1995). Hermann et al. (1999) demonstrated a similar inhibitory
effect by intravenous administration of LPS. This inhibitory effect of LPS on
TRH-induced gastric motility was reversed when endogenous TNF-α
production was selectively suppressed (Hermann et al., 1999). Additionally, intravenous injections of bethanechol, a peripheral cholinergic ago-
nist, were still able to elicit usual increases in gastric motility in the LPS
model. These experiments confirmed that the inhibition of TRH-induced
gastric motility seen in the LPS model was due to the central effects of
endogenously produced proinflammatory cytokines, primarily TNF-α.
Behavioral and physiological responses to LPS are achieved by
communication of cytokine signals via vagal afferents to brain stem
centers and further to the hypothalamus via catecholaminergic and other
brainstem pathways (Fig. 1). The brain stem and hypothalamic centers
coordinate the responses of various neuromodulators including TRH to the
cytokine signals. These responses are then communicated to the periphery
via vagal efferents and probably other, so far, unknown pathways.
5.3. Experimental evidence for vagus-independent
thyrotropin-releasing hormone–immune system interactions
Vagal afferents clearly play a major role in the communication of
immune signals from the periphery to the CNS. However, vagotomy
Table 1
Comparison of cytokine-induced sickness effects with clinical effects of TRH
Domains
Cytokine-induced sickness
modela
Neurovegetative Fatigue, psychomotor
retardation, sleep alterations,
anorexia
Cognitive
Decreased attention and
concentration, memory
difficulties
Affective
Depressed mood, anxiety,
anhedonia
Somatic
Pain, gastrointestinal
disturbances
In-vivo TRH effectsb
Arousal, vigilance, reversal of
sedation, improved motor
function
Improved cognition including
improved memory
Antidepressant effects, improved
emotional lability
Pain modulation, gastric
cytoprotective effects
a
From animal models and human use of cytokines (see Dantzer and Kelley, 2007 and
Raison et al., 2006 for details).
b
Based on the in vivo data in animal models and human use (see Gary et al., 2003 and
Yarbrough et al., 2007 for details).
J. Kamath et al. / Pharmacology & Therapeutics 121 (2009) 20–28
25
Fig. 2. TRH and immune system interactions in health and disease; focus on LPS/cytokine-induced sickness response.
was shown to block the behavioral (i.e. decreased social exploration)
effects of IL-1β injected intraperitonially but not intravenously,
suggesting that there are alternative pathways by which the cytokines
can mediate effects on the CNS (Bluthé et al., 1996). Similarly, intraperitoneal IL-1β or LPS-induced physiological and behavioral
responses were only slightly attenuated in subdiaphragmatically
vagotomized rats (Wieczorek et al., 2005). Porter et al. (1998) showed
that neither the vagal nor the nonvagal (splanchnic) afferent nerves
from the upper gut are necessary for the anorexia produced by intraperitoneal IL-1β and LPS. Similar to the vagal afferents, the brainstem
catecholaminergic pathways play a role in the activation of hypothalamic CRH neurons during the LPS-induced immune response
(Ericsson et al., 1994). However, Fekete et al. (2005) showed that
these brainstem pathways are not required in the LPS-induced suppression of TRH in the PVN.
In a comprehensive review, Wittman (2008) suggests that the
brainstem–catecholamine neurons–PVN pathway is necessary for the
increase in CRH, but not for the TRH suppression in the LPS paradigm. It
is important to note that, despite their large molecular size, cytokines
can be transported into the brain, endogenously synthesized in the
brain, or transmit signals to the brain via mechanisms independent of
vagal afferents (Pavlov & Tracey, 2004). Wittman (2008) suggests that
the suppression of TRH in the PVN occurs as the result of direct effects
of proinflammatory cytokines, which may involve negative feedback
due to increased local T3 production, as discussed earlier (Boelen et al.,
2006). From an evolutionary perspective, it may be important to have a
direct pathway for suppression of TRH (Fig. 1). The suppression of TRH
may be necessary for survival during an adaptive sickness response
(Kelley et al., 2003).
5.4. Role of thyrotropin-releasing hormone
in the pathophysiology of the inflammatory process
Both in vitro and in vivo evidence suggests that cytokine signaling to the brain may involve direct suppression of TRH by the proinflammatory cytokines in key brain centers such as the PVN and the
DVC. The findings reviewed above suggest a major role for TRH in the
core pathophysiology of the LPS-induced immune response. Suppres-
sion of TRH may represent one of the critical events during an
inflammatory process. It may be the event that drives the behavioral
changes (e.g. social withdrawal, fatigue) and physiological changes
that are typical of the cytokine-induced sickness response.
The numerous clinical actions of TRH and TRH analogs (see Gary
et al., 2003 and Yarbrough et al., 2007 for comprehensive reviews)
such as arousal induction, enhancing cognitive function, improving
motor function, and increasing gastric motility seem to be opposite
to what is observed in the cytokine-induced sickness behavior
paradigm (Table 1). The suppression of TRH seen in the LPS/proinflammatory cytokine model is consistent with the behavioral and
physiological effects seen in the cytokine-induced sickness model
(Fig. 2).
In summary, the accumulated evidence (Fig. 1 and Table 2)
strongly suggests significant suppressive effects of pro-inflammatory
cytokines on TRH systems throughout the HPT axis during an
inflammatory process. The suppressive effects on TRH are observed
both in the hypothalamus (PVN) and in the brainstem (DVC) via or
independent of vagal pathways. The clinical actions of TRH (Table 1)
combined with the strong suppressive effects of proinflammatory
cytokines on TRH systems during an inflammatory process suggest a
potential role for TRH-based therapeutics in certain inflammatory
disorders (Fig. 2).
6. Thyrotropin-releasing
hormone-based therapeutics in inflammatory disorders
The recognition and delineation of “proinflammatory cytokineinduced sickness behavior” has advanced the field of psychoimmunology in many ways. Dantzer and Kelley (2007) suggest that the common
symptoms of sickness driven by proinflammatory cytokines – fatigue,
anorexia, sleepiness, withdrawal from social activities, gastric stasis,
fever, aching joints – are part of a “relative homeostasis” as a survival
response to the trigger (e.g. infection). This acute sickness response is no
longer adaptive if it is out of proportion to the insult or is unnecessarily
prolonged (Elenkov et al., 2005). Increasing evidence suggests that such
out of proportion or prolonged sickness behavior occurs in many
disorders and inflicts serious physical and emotional consequences. One
26
J. Kamath et al. / Pharmacology & Therapeutics 121 (2009) 20–28
possible cause is the use of cytokines (interferons or interleukins) to
treat certain types of cancers and hepatitis C (Raison et al., 2006). Other
causes include the autoimmune disorders (e.g. rheumatoid arthritis,
psoriasis, multiple sclerosis, ankylosing spondilytis, and inflammatory
bowel diseases) (Elenkov et al., 2005). The prolonged sickness syndrome
also has been observed after chemotherapy or radiation for cancer and
after myocardial infarction (Kelley et al., 2003; Elenkov et al., 2005). The
fatigue and depression observed in a subpopulation of patients with
these disorders has been associated with a chronic inflammatory
process (Miller et al., 2008). A number of recent studies associated
the idiopathic fatigue reported by cancer patients with increase in
specific pro-inflammatory cytokine levels (Bower, 2007). Even local
radiation treatments in otherwise healthy cancer patients can cause
significant fatigue. This radiation-induced fatigue has also been
associated with increased plasma pro-inflammatory cytokine concentrations in patients with cancer (Jacobsen & Thors, 2003). Marquette
et al. (2003) showed that the hypothalamus and certain other areas of
Table 3
Future investigations of TRH-immune system interactions (not an exhaustive list)
In vitro
In vivo in animal
models
Table 2
Experimental evidence of bi-directional interactions between TRH and immune system
Stimulating effects
– TRH stimulated thymocyte cell
proliferation and inhibited
prednisolone-induced thymus
involutiona
– TRH stimulated splenocyte
proliferationa
– Thymectomy caused depressed
thyroid function and decreased TRH,
TSH levels⁎
– TRH enhanced T cell dependent,
antigen induced antibody response
– TRH stimulated IFN-α production
by human peripheral blood
mononuclear cells
In vivo in – Central TRH analogue
administration caused gastric
animal
hyperemia via degranulation of mast
models
cells
– Central TRH analogue
administration increased gastric,
pancreatic and hepatic blood flow
– Central TRH analogue
administration enhanced gastric
motor and secretory function ⇒
showed ulcerogenic potential
– T cell dependent antigen response:
In the early phase (b 24 h) showed
increased hypothalamic TRH levels
(required for adequate antibody
production)
In vitro
In vivo in – Intravenous TRH showed
humans
stimulatory effect on IFN-γ and IL-2
levels in healthy subjects
a
In developmental stages.
Inhibitory effects
– TRH suppressed spontaneous
splenocyte proliferationa
– TRH caused decreased IgG
production and inhibited monocytes
– Mitogen-stimulated human whole
blood cells when incubated with
TRH and imipramine showed
suppression of IFN-γ and IL-10
production
– TRH showed protective effect in
mice challenged with
encephalomyelitis virus
– Centrally administered TRH
analogue showed protective effects
in cerulin-induced pancreatitis
– Central TRH analogue
administration ⇒ showed
cytoprotective effects in ethanolinduced gastric ulcers
– Central administration (in DVC) of
IL-1β and TNF-α blocked TRHinduced gastric motility
– Intravenous LPS administration
blocked TRH-induced gastric
motility
– Intravenous LPS administration
caused suppression of hypothalamic
TRH
– Intraperitoneal IL-1 and
intravenous TNF-α caused
suppression of hypothalamic pro
TRH mRNA levels
– Intravenous IL-6 inhibited TRHstimulated prolactin secretion
– T cell dependent antigen response:
In the late phase (N24 h) showed
suppression of hypothalamic TRH
levels
– Intravenous TRH caused decreased
IL-2 levels in patients with
hypothyroidism with baseline high
IL-2 levels
– Intravenous and intralymphatic
vessel administration of TRH showed
therapeutic effects in the treatment
of acute pancreatitis
In vivo in
humans
– Investigation of TRH role in the development of organs/tissues
with autocrine/paracrine TRH networks
– Investigation of TRH role and source in the peripheral organs/
tissues with autocrine/paracrine TRH networks
– Investigation of differential expression of TRH-R1 and TRH-R2
receptors in the immune system and in other peripheral organs
with TRH networks
– Effects of TRH on immune cells and on cytokine production in
immunosuppressed state
– Investigation of development of TRH system/HPT axis in the
inflammatory vs. immunosuppressed state
– Investigation of TRH system in the immunosuppressed state of
the fully developed immune system
– Behavioral and other effects of TRH in the inflammatory vs.
immunosuppressed state
– Behavioral and other effects of receptor specific TRH analogs
(TRH-R1 vs. TRH-R2) on the immune system in general and in the
inflammatory vs. immunosuppressed state
– Investigation of TRH interactions with other critical
neuromodulators (i.e. CRF, vasopressin, prolactin) in differential
immune states
– Investigation of TRH-induced immunomodulatory effect in select
disorders (for example acute pancreatitis, spinal chord injury, and
Alzheimer's disease) and its contribution to the therapeutic effects
associated with TRH and its analogs in these disorders
– Investigation of therapeutic effects of TRH and receptor specific
TRH analogs in select animal models of inflammatory disorders
– Investigation of immune system in the hyper vs. hypothyroid
states
– Investigation of TRH system/HPT axis in the immunosuppressed
state
– Investigation of therapeutic effects of TRH and its analogs in
select inflammatory disorders
the brain of partial-body irradiated rats show high levels of proinflammatory cytokines, specifically IL-1β, TNF-α, and IL-6. This increase
in cytokine levels was prevented by vagotomy before irradiation,
confirming the importance of the vagal pathway for cytokine signaling
(Marquette et al., 2003).
6.1. Cytokine-induced sickness syndrome as
a therapeutic target in inflammatory disorders
Corticosteroids, known to suppress the inflammatory process, are
frequently used in palliative treatment for their anti-fatigue, anticachexia and anti-anorexia effects (Shih & Jackson, 2007). The first
identification of the “sickness syndrome” as a therapeutic target came
from the behavioral data generated by the clinical use of TNF
inhibitors (recombinant soluble form of TNF receptor). The introduction of these new anti-TNF drugs (etanercept, infliximab, and
adalimumab) has significantly advanced the field of rheumatology.
These drugs treat not only the specific aspects of an illness but also
cause an overall improvement in patient functioning and quality of
life. In clinical studies with these agents, patients reported less fatigue,
improved physical function and better emotional and mental function
(Nash & Florin, 2005). The “anti-sickness” effects of these agents have
been reported in an array of autoimmune diseases including
rheumatoid arthritis, ankylosing spondylitis, Wegeners granulomatosis, psoriasis, and inflammatory bowel diseases (Nash & Florin,
2005). In a recent pilot study, Monk et al. (2006) confirmed antifatigue effects of etanercept in cancer patients undergoing chemotherapy. Unfortunately, these agents have been associated with
significant side effects. For some of these agents, the Food and Drug
Administration has added a “black box” warning of risk of serious
infections (Rychly & DiPiro, 2005). Thus, more specific therapeutic
agents are needed to counteract the behavioral consequences of
autoimmune disorders. TRH-based therapeutics may provide one
such approach based on the hypothesis that some of the behavioral
J. Kamath et al. / Pharmacology & Therapeutics 121 (2009) 20–28
symptoms of inflammatory disorders are due to the suppressive
effects of cytokines on TRH systems. This hypothesis needs further
evaluation in in vitro and in vivo settings.
6.2. Challenges and advances in the development
of thyrotropin-releasing hormone-based therapeutics
The development of TRH-based therapeutics has been hampered
by the short half-life of TRH and its limited access to the CNS after
peripheral administration. However, it is important to emphasize that,
in contrast to the recent novel treatments for inflammatory disorders
(i.e. TNF blockers) with potentially serious side effects, TRH has been
in clinical use since 1974. It has a favorable safety record both in
clinical use and in research studies, including studies in patients with
serious illnesses (Gary et al., 2003; Yarbrough et al., 2007). Given the
limitations of native TRH, it is important to utilize metabolically stable
TRH analogs with better access to the CNS. Two TRH analogs, TA-0910
(Ceredist) and CG-3703, possessing these properties, have shown
clinical promise (Gary et al., 2003). Ceredist has been used in Japan
since 2001 for the treatment of spinocerebellar degeneration. Clinical
investigations can be conducted to test these and related compounds
for the treatment of behavioral and other aspects of certain inflammatory disorders (i.e. autoimmune diseases, inflammatory bowel
diseases, cancer-related fatigue or depression, and Alzheimer's
disease). Additionally, the development of new TRH analogs, especially receptor subtype selective compounds, represents an area of
significant research potential.
7. Future investigations
Future investigations should include evaluation of TRH-based
therapeutics in inflammatory disorders, especially for the behavioral
aspects of the sickness syndrome associated with these disorders. On a
conceptual level, it is important to investigate whether the homeostatic role for TRH in the CNS put forth by Gary et al. (2003) extends to
the regulation of the immune system. Studies to evaluate the
differential roles of the two types of TRH receptors in TRH-immune
system interactions are also a matter of high priority. As mentioned
earlier, TRH and TRH analogs have shown clinical promise in certain
disorders (Gary et al., 2003). Many of these disorders are associated
with inflammatory processes, and immunomodulation may play a role
in the therapeutic effects associated with TRH or its analogs. It is
important to test this hypothesis in animal models of these disorders.
Potential experiments to investigate these hypotheses are described in
Table 3.
8. Conclusions
TRH has numerous interactions with the immune system in the
CNS as well as in the periphery and during multiple stages of development. These interactions can be direct or indirect, i.e. via other
neuromodulators. A large body of in vitro and in vivo evidence supports a homeostatic role for TRH in its interactions with the immune
system, extending the hypothesis previously proposed by Gary et al.
(2003) and Yarbrough et al. (2007) of a homeostatic regulatory role for
TRH to include effects on immune system function.
The TRH-immune system homeostatic hypothesis states that TRHmediated mechanisms respond to many elements of the immune
system and affect them in ways that tend to maintain or restore
homeostasis. Some aspects of this hypothesis may be tested by the use
of TRH or its congeners to treat patients with certain inflammatory
diseases or to affect animal models of those diseases. The critical role
of TRH in the cytokine-induced sickness paradigm presents excellent
opportunities for further exploration of this hypothesis and provides
promising targets for TRH-based therapeutics of immune systemrelated medical and psychiatric disorders.
27
References
Ader, R. (1980). Presidential address: psychosomatic and psychoimmunologic research.
Psychosom Med 42, 307−322.
Bayliss, D. A., Viana, F., Kanter, R. K., Szymeczek-Seay, C. L., Berger, A. J., & Millhorn, D. E.
(1994). Early postnatal development of thyrotropin-releasing hormone (TRH)
expression, TRH receptor binding, and TRH responses in neurons of rat brainstem.
J Neurosci 14(2), 821−833.
Ben-Jonathan, N., Mershon, J., Allen, D., & Steinmetz, R. (1996). Extrapituitary prolactin:
distribution, regulation, functions and clinical aspects. Endocr Rev 17, 639−669.
Bilek, R. (2000). TRH-like peptides in prostate gland and other tissues. Physiol Res 49
(Suppl 1), 519−526.
Błaszkowska, J., Pawlikowski, M., Komorowski, J., & Kurnatowski, P. (2004). Effect of
thyroliberin on the course of experimental candidosis in mice. Mycoses 47(3–4),
115−120.
Bluthé, R. M., Michaud, B., Kelley, K. W., & Dantzer, R. (1996). Vagotomy blocks
behavioral effects of interleukin-1 injected via the intraperitoneal route but not via
other systemic routes. Neuroreport 7(15–17), 2823−2827.
Boelen, A., Kwakkel, J., Thijssen-Timmer, D. C., Alkemade, A., Fliers, E., & Wiersinga, W. M.
(2004). Simultaneous changes in central and peripheral components of the
hypothalamus–pituitary–thyroid axis in lipopolysaccharide-induced acute illness
in mice. J Endocrinol 182(2), 315−323.
Boelen, A., Kwakkel, J., Wiersinga, W. M., & Fliers, E. (2006). Chronic local inflammation
in mice results in decreased TRH and type 3 deiodinase mRNA expression in the
hypothalamic paraventricular nucleus independently of diminished food intake.
J Endocrinol 191(3), 707−714.
Bower, J. E. (2007). Cancer-related fatigue: links with inflammation in cancer patients
and survivors. Brain Behav Immun 21(7), 863−871.
Dantzer, R., & Kelley, K. W. (2007). Twenty years of research on cytokine-induced
sickness behavior. Brain Behav Immun 21(2), 153−160.
Elenkov, I. J., Iezzoni, D. G., Daly, A., Harris, A. G., & Chrousos, G. P. (2005). Cytokine
dysregulation, inflammation and well-being. Neuroimmunomodulation 12(5),
255−269.
Ericsson, A., Kovács, K. J., & Sawchenko, P. E. (1994). A functional anatomical analysis of
central pathways subserving the effects of interleukin-1 on stress-related
neuroendocrine neurons. J Neurosci 14(2), 897−913.
Eskandari, F., & Sternberg, E. M. (2002). Neural-immune interactions in health and
disease. Ann N Y Acad Sci 966, 20−27.
Fekete, C., Singru, P. S., Sarkar, S., Rand, W. M., & Lechan, R. M. (2005). Ascending
brainstem pathways are not involved in lipopolysaccharide-induced suppression of
thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus. Endocrinology 146(3), 1357−1363.
Fukusumi, S., Ogi, K., Onda, H., & Hinuma, S. (1995). Distribution of thyrotropinreleasing hormone receptor mRNA in rat peripheral tissues. Regul Pept 57(2),
115−121.
Gary, K. A., Sevarino, K. A., Yarbrough, G. G., Prange, A. J., Jr., & Winokur, A. (2003). The
thyrotropin-releasing hormone (TRH) hypothesis of homeostatic regulation:
implications for TRH-based therapeutics. J Pharmacol Exp Ther 305(2), 410−416.
Gaykema, R. P., Chen, C. C., & Goehler, L. E. (2007). Organization of immune-responsive
medullary projections to the bed nucleus of the stria terminalis, central amygdala,
and paraventricular nucleus of the hypothalamus: evidence for parallel viscerosensory pathways in the rat brain. Brain Res 1130(1), 130−145.
Gershengorn, M. C., & Osman, R. (1996). Molecular and cellular biology of thyrotropinreleasing hormone receptors. Physiol Rev 76(1), 175−191.
Grasso, G., Massai, L., De Leo, V., & Muscettola, M. (1998). The effect of LHRH and TRH on
human interferon-gamma production in vivo and in vitro. Life Sci 62(22),
2005−2014.
Guillemin, R. (1978). Peptides in the brain: the new endocrinology of the neuron.
Science 202, 390−402.
Hart, R., Wagner, F., Steffens, W., Lersch, C., Dancygier, H., Duntas, L., et al. (1990). Effect
of thyrotropin-releasing hormone on immune functions of peripheral blood
mononuclear cells. Regul Pept 27(3), 335−342.
Hermann, G., & Rogers, R. C. (1995). Tumor necrosis factor-alpha in the dorsal vagal
complex suppresses gastric motility. Neuroimmunomodulation 2(2), 74−81.
Hermann, G. E., Tovar, C. A., & Rogers, R. C. (1999). Induction of endogenous tumor
necrosis factor-alpha: suppression of centrally stimulated gastric motility. Am
J Physiol 276(1 Pt 2), R59−68.
Heuer, H., Schäfer, M. K., O'Donnell, D., Walker, P., & Bauer, K. (2000). Expression of
thyrotropin-releasing hormone receptor 2 (TRH-R2) in the central nervous system
of rats. J Comp Neurol 428(2), 319.
Jacobsen, P. B., & Thors, C. L. (2003). Fatigue in the radiation therapy patient: current
management and investigations. Semin Radiat Oncol 13(3), 372−380.
Kawakubo, K., Akiba, Y., Adelson, D., Guth, P. H., Engel, E., Taché, Y., et al. (2005). Role of
gastric mast cells in the regulation of central TRH analog-induced hyperemia in rats.
Peptides 26(9), 1580−1589.
Keller, S. E., Schleifer, S. J., Liotta, A. S., Bond, R. N., Farhoody, N., & Stein, M. (1988). Stressinduced alterations of immunity in hypophysectomized rats. Proc Natl Acad Sci U S A
85(23), 9297−9301.
Kelley, K. W., Bluthé, R. M., Dantzer, R., Zhou, J. H., Shen, W. H., Johnson, R. W., et al.
(2003). Cytokine-induced sickness behavior. Brain Behav Immun 17(Suppl 1),
S112−118.
Kelley, K. W., Weigent, D. A., & Kooijman, R. (2007). Protein hormones and immunity.
Brain Behav Immun 21(4), 384−392.
Klein, J. R. (2003). Physiological relevance of thyroid stimulating hormone and
thyroid stimulating hormone receptor in tissues other than the thyroid. Autoimmunity
36(6–7), 417−421.
28
J. Kamath et al. / Pharmacology & Therapeutics 121 (2009) 20–28
Klein, J. R. (2006). The immune system as a regulator of thyroid hormone activity. Exp
Biol Med (Maywood) 231(3), 229−236.
Komorowski, J., Stepień, H., & Pawlikowski, M. (1993). The evidence of thyroliberin/
triiodothyronine control of TSH secretory response from human peripheral blood
monocytes cultured in vitro. Neuropeptides 25(1), 31−34.
Komorowski, J., Stepien, H., & Pawlikowski, M. (1994). Increased interleukin-2 levels
during standard TRH test in man. Neuropeptides 27, 151−156.
Kruger, T. E. (1996). Immunomodulation of peripheral lymphocytes by hormones of the
hypothalamus–pituitary–thyroid axis. Adv Neuroimmunol 6(4), 387−395.
Kubera, M., Kenis, G., Bosmans, E., Jaworska-Feil, L., Lasoń, W., Scharpe, S., et al. (2000).
Suppressive effect of TRH and imipramine on human interferon-gamma and
interleukin-10 production in vitro. Pol J Pharmacol 52(6), 481−486.
Kruger, T. E., Smith, L. R., Harbour, D. V., & Blalock, J. E. (1989). Thyrotropin:an
endogenous regulator of the in vitro immune response. J Immunol 142(3), 744−747.
Kunert-Radek, J., Pawlikowski, M., Stepien, H., & Janecka, A. (1991). Inhibitory effect of
thyrotropin releasing hormone on spontaneous proliferation of mouse spleen
lymphocytes in vitro. Biochem Biophys Res Commun 181(2), 562−565.
Lechan, R. M. (1993). Update on thyrotropin-releasing hormone. Thyroid Today 16, 1−11.
Lesnikov, V. A., Korneva, E. A., Dall'ara, A., & Pierpaoli, W. (1992). The involvement of
pineal gland and melatonin in immunity and aging: II. Thyrotropin-releasing
hormone and melatonin forestall involution and promote reconstitution of the
thymus in anterior hypothalamic area (AHA)-lesioned mice. Int J Neurosci 62(1–2),
141−153.
Lynn, R. B., Feng, H. S., Han, J., & Brooks, F. P. (1991). Gastric effects of thyrotropinreleasing hormone microinjected into the dorsal vagal nucleus in cats. Life Sci 48(13),
1247−1254.
Marquette, C., Linard, C., Galonnier, M., Van Uye, A., Mathieu, J., Gourmelon, P., et al.
(2003). IL-1beta, TNFalpha and IL-6 induction in the rat brain after partial-body
irradiation: role of vagal afferents. Int J Radiat Biol 79(10), 777−785.
Martino, E., Nardi, M., Vaudagna, G., Simonetti, S., Cilotti, A., Piunchera, A., et al. (1980).
Thyrotropin-releasing hormone-like material in human retina. J Endocrinol Invest 3,
267−271.
Matre, V., Høvring, P. I., Fjeldheim, A. K., Helgeland, L., Orvain, C., Andersson, K. B., et al.
(2003). The human neuroendocrine thyrotropin-releasing hormone receptor
promoter is activated by the haematopoietic transcription factor c-Myb. Biochem
J 372(Pt 3), 851−859.
Mellado, M., Fernández-Agulló, T., Rodríguez-Frade, J. M., San Frutos, M. G., de la Peña, P.,
Martínez-A, C., et al. (1999). Expression analysis of the thyrotropin-releasing
hormone receptor (TRHR) in the immune system using agonist anti-TRHR
monoclonal antibodies. FEBS Lett 28(451(3)), 308−314.
Miller, A. H., Ancoli-Israel, S., Bower, J. E., Capuron, L., & Irwin, M. R. (2008).
Neuroendocrine-immune mechanisms of behavioral comorbidities in patients
with cancer. J Clin Oncol 26(6), 971−982.
Monk, J. P., Phillips, G., Waite, R., Kuhn, J., Schaff, L. J., Otterson, G. A., et al. (2006).
Assessment of tumor necrosis factor alpha blockade as an intervention to improve
tolerability of dose-intensive chemotherapy in cancer patients. J Clin Oncol 24(12),
1852−1859.
Montagne, J. J., Ladram, A., Grouselle, D., Nicolas, P., & Bulant, M. (1997). Thyrotropinreleasing hormone immunoreactivity in rat adrenal tissue is localized in mast cells.
J Histochem Cytochem 45(12), 1623−1627.
Montagne, J. J., Ladram, A., Nicolas, P., & Bulant, M. (1999). Cloning of thyrotropinreleasing hormone precursor and receptor in rat thymus, adrenal gland, and testis.
Endocrinology 140(3), 1054−1059.
Morrow, N. S., Quinonez, G., Weiner, H., Taché, Y., & Garrick, T. (1995). Interleukin-1 beta
in the dorsal vagal complex inhibits TRH analogue-induced stimulation of gastric
contractility. Am J Physiol 269(2 Pt 1), G196−202.
Nagy, E., & Berczi, I. (1978). Immunodeficiency in hypophysectomized rats. Acta
Endocrinol 89(3), 530.
Nash, P. T., & Florin, T. H. (2005). Tumour necrosis factor inhibitors. Med J 183(4),
205−208.
Nillni, E. A., & Sevarino, K. A. (1999). The biology of pro-thyrotropin-releasing hormonederived peptides. Endocr Rev 20(5), 599−648.
Pang, X. P., Hershman, J. M., Mirell, C. J., & Pekary, A. E. (1989). Impairment of
hypothalamic-pituitary–thyroid function in rats treated with human recombinant
tumor necrosis factor-alpha (cachectin). Endocrinology 125(1), 76−84.
Pavlov, V. A., & Tracey, K. J. (2004). Neural regulators of innate immune responses and
inflammation. Cell Mol Life Sci 61(18), 2322−2331.
Pawlikowski, M., Stepien, H., & Komorowski, J. (1994). Hypothalamic-pituitary–thyroid
axis and the immune system. Neuroimmunomodulation 1(3), 149−152.
Pawlikowski, M., Zerek-Mełeń, G., & Winczyk, K. (1992). Thyroliberin (TRH) increases
thymus cell proliferation in rats. Neuropeptides 23(3), 199−202.
Pekary, A. E., Stevens, S. A., & Sattin, A. (2007). Lipopolysaccharide modulation of
thyrotropin-releasing hormone (TRH) and TRH-like peptide levels in rat brain and
endocrine organs. J Mol Neurosci 31(3), 245−259.
Perez, C. C., Penaleva, R., Paez, P. M., Renner, U., Reul, J. M., Stalla, G. K., et al. (1999). Early
activation of thyrotropin-releasing-hormone and prolactin plays a critical role
during a T cell-dependent immune response. Endocrinology 140(2), 690−697.
Pierpaoli, W., & Yi, C. (1990). The involvement of pineal gland and melatonin in
immunity and aging. I. Thymus-mediated, immunoreconstituting and antiviral
activity of thyrotropin-releasing hormone. J Neuroimmunol 27(2–3), 99−109.
Porter, M. H., Hrupka, B. J., Langhans, W., & Schwartz, G. J. (1998). Vagal and splanchnic
afferents are not necessary for the anorexia produced by peripheral IL-1beta, LPS,
and MDP. Am J Physiol 275(2 Pt 2), R384−389.
Raiden, S., Polack, E., Nahmod, V., Labeur, M., Holsboer, F., & Arzt, E. (1995). TRH receptor
on immune cells: in vitro and in vivo stimulation of human lymphocyte and rat
splenocyte DNA synthesis by TRH. J Clin Immunol 15(5), 242−249.
Raison, C. L., Capuron, L., & Miller, A. H. (2006). Cytokines sing the blues: inflammation
and the pathogenesis of depression. Trends Immunol 27(1), 24−31.
Rychly, D. J., & DiPiro, J. T. (2005). Infections associated with tumor necrosis factor-alpha
antagonists. Pharmacotherapy 25(9), 1181−1192.
Santos, J., Saperas, E., Mourelle, M., Antolín, M., & Malagelada, J. R. (1996). Regulation of
intestinal mast cells and luminal protein release by cerebral thyrotropin-releasing
hormone in rats. Gastroenterology 111(6), 1465−1473.
Sawchenko, P. E., Li, H. Y., & Ericsson, A. (2000). Circuits and mechanisms governing
hypothalamic responses to stress: a tale of two paradigms. Prog Brain Res 122,
61−78.
Schettini, G., Grimaldi, M., Landolfi, E., Meucci, O., Ventra, C., Florio, T., et al. (1991). Role
of interleukin-6 in the neuroendocrine system. Acta Neurol (Napoli) 13(4), 361−367.
Serebrov, V., Zobnina, M. N., & Tikhonova, N. M. (1992). Structural–functional state of
the thyroid gland after thymectomy. Biull Eksp Biol Med 114(9), 329−332.
Shih, A., & Jackson, K. C., 2nd (2007). Role of corticosteroids in palliative care. J Pain
Palliat Care Pharmacother 21(4), 69−76.
Shimanko, I. I., Limarev, V. M., Ashmarin, I. P., Lelekova, T. V., & Sanzhieva, L. T. (1992).
The use of thyrotropin-releasing hormone in clinical practice as a lymphatic
stimulator in the treatment of acute pancreatitis. Khirurgiia (Mosk)(1), 64−66.
Stephens, R. L., Ishikawa, T., Weiner, H., Novin, D., & Tache, Y. (1988). TRH analogue, RX
77368, injected into dorsal vagal complex stimulates gastric secretion in rats. Am
J Physiol 254(5 Pt 1), G639−643.
Sternberg, E. M. (1995). Neuroendocrine factors in susceptibility to inflammatory disease:
focus on the hypothalamic-pituitary–adrenal axis. Horm Res 43(4), 159−161.
Sun, Y., Lu, X., & Gershengorn, M. C. (2003). Thyrotropin-releasing hormone receptors —
similarities and differences. J Mol Endocrinol 30(2), 87−97.
Taché, Y., & Yoneda, M. (1993). Central action of TRH to induce vagally mediated gastric
cytoprotection and ulcer formation in rats. J Clin Gastroenterol 17(Suppl 1), S58−63.
Taché, Y., Yang, H., Miampamba, M., Martinez, V., & Yuan, P. Q. (2006). Role of brainstem
TRH/TRH-R1 receptors in the vagal gastric cholinergic response to various stimuli
including sham-feeding. Auton Neurosci 125(1–2), 42−52.
Trejbal, D., Petrasova, D., & Wagnerova, H. (2001). Prolactin and interleukin 2
concentrations before and after i.v. TRH application in primary hypothyroidism
and in controls. Bratisl Lek Listy 102(9), 417−419.
van Haasteren, G. A., van der Meer, M. J., Hermus, A. R., Linkels, E., Klootwijk, W.,
Kaptein, E., et al. (1994). Different effects of continuous infusion of interleukin-1
and interleukin-6 on the hypothalamic-hypophysial-thyroid axis. Endocrinology
135(4), 1336−1345.
Wang, J., & Klein, J. R. (1995). Hormonal regulation of extrathymic gut T cell
development: involvement of thyroid stimulating hormone. Cell Immunol 161(2),
299−302.
Wang, J., Whetsell, M., & Klein, J. R. (1997). Local hormone networks and intestinal T cell
homeostasis. Science 275(5308), 1937−1939.
Winokur, A., & Utiger, R. D. (1974). Thyrotropin-releasing hormone: regional distribution in rat brain. Science 185, 265−266.
Wittman, G. J. (2008). Regulation of hypophysiotropic corticotropin-releasing hormone
and thyrotropin-releasing hormone-synthesizing neurons by brainstem catecholaminergic neurons. Neuroendocrinol 0(7), 952−960.
Wieczorek, M., Swiergiel, A. H., Pournajafi-Nazarloo, H., & Dunn, A. J. (2005).
Physiological and behavioral responses to interleukin-1beta and LPS in vagotomized mice. Physiol Behav 85(4), 500−511.
Winczyk, K., & Pawlikowski, M. (2000). Time of day-dependent effects of thyroliberin
and thyrotropin on thymocyte proliferation in rats. Neuroimmunomodulation 7(2),
89−91.
Yamada, M., Shibusawa, N., Hashida, T., Ozawa, A., Monden, T., Satoh, T., et al. (2000).
Expression of thyrotropin-releasing hormone (TRH) receptor subtype 1 in mouse
pancreatic islets and HIT-T15, an insulin-secreting clonal beta cell line. Life Sci 66(12),
1119−1125.
Yarbrough, G. G. (1979). On the neuropharmacology of thyrotropin releasing hormone
(TRH). Prog Neurobiol 12(3–4), 291−312.
Yarbrough, G. G., Kamath, J., Winokur, A., & Prange, A. J., Jr (2007). Thyrotropin-releasing
hormone (TRH) in the neuroaxis: therapeutic effects reflect physiological functions
and molecular actions. Med Hypotheses 69(6), 1249−1256.
Yoneda, M., Hoshimoto, T., Nakamura, K., Tamori, K., Yokohama, S., Kono, T., et al. (2003).
Thyrotropin-releasing hormone in the dorsal vagal complex stimulates hepatic
blood flow in rats. Hepatology 38(6), 1500−1507.
Yoneda, M., Goto, M., Nakamura, K., Yokohama, S., Kono, T., Tanamo, M., et al. (2005).
Thyrotropin-releasing hormone in the dorsal vagal complex stimulates pancreatic
blood flow in rats. Regul Pept 131(1–3), 74−81.
Yoneda, M., Goto, M., Nakamura, K., Shimada, T., Hiraishi, H., Terano, A., et al. (2005).
Protective effect of central thyrotropin-releasing hormone analog on ceruleininduced acute pancreatitis in rats. Regul Pept 125(1–3), 119−124.
Yu-Lee, L. Y. (2002). Prolactin modulation of immune and inflammatory responses.
Recent Prog Horm Res 57, 435−455.