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Sebaceous Gland in Human Skin ^ The
Fantastic Future of a Skin Appendage
COMMENTARY
See related article on page 905
Christos C. Zouboulis
Department of Dermatology, University Medical Center, Benjamin Franklin, The Free University of Berlin, Berlin, Germany
colleagues have shown that all enzymes required for utilizing
cholesterol as a substrate for steroidogenesis are present in human
sebocytes with P450 side chain cleavage enzyme, adrenodoxin reductase, and P450c17 expressed in the cytoplasm, whereas steroidogenic factor-1 exhibited perinuclear or nuclear localization. In
addition, they found that sebocytes converted 22-hydroxycholesterol to 17-hydroxypregnenolone. These results, together with
previous data suggesting a major role of sebocytes in the conversion of dehydroepiandrosterone to the potent androgens testosterone and 5a-dihydrotestosterone (Thiboutot et al, 1995, 1998;
Chen et al, 1998; Fritsch et al, 2001), indicate that the skin is, indeed, a steroidogenic tissue to be added to the list including the
classical ones, adrenal gland and gonads, as well as placenta, brain,
and intestine. Moreover, the responsible skin compartment for
both the initiation of steroidogenesis and the local production of
potent androgens seems to be the sebaceous gland.
This wealth of new fascinating data would not be acquired
without the existence of adequate experimental models. Since sebaceous gland di¡erentiation is extremely species-speci¢c, human
models are required. After the less successful e¡orts by Kellum
(1966) and Karasek and Charlton (1977) to develop models for
the investigation of the human sebaceous glands, Kealey et al
(1996) and Xia et al (1989) introduced the maintenance of the sebaceous gland ex vivo and the cultivation of sebaceous gland cells
in vitro, respectively (reviewed in Zouboulis et al, 1991, 1999). Several modi¢cations of the technique of Xia et al (1989) have facilitated the reproducible cultivation of human sebocytes in vitro.
However, human sebocytes are predisposed to di¡erentiate by accumulating neutral fat droplets until they burst and die. Therefore, adequate cell amounts for large scale experiments can only
be obtained from multiple donors, while prolonged experiments
are hindered by the short life span of the cells. To overcome this
problem, Zouboulis et al (1999) transfected human facial sebocytes with Simian Virus- 40 large T antigen and immortalized
them. The resulting patented cell line, termed SZ95, has been
cloned and further investigated, was shown to retain major characteristics of normal human sebocytes, such as di¡erentiation
with increase of cell volume and lipid synthesis and subsequent
apoptosis, expression of characteristic origin- and function-speci¢c proteins of human sebaceous glands, and expected biological
response to androgens and retinoids (Zouboulis et al, 1999; Wro¤bel
et al, 2003), and has been widely used in skin research since then.
To perform their experiments, Thiboutot and colleagues have
applied the transfection system used by Zouboulis et al (1999) to
develop a second immortalized human facial sebaceous gland cell
line, termed SEB-1. Like SZ95 sebocytes, SEB-1 sebocytes also
express characteristic sebaceous gland proteins and their cytoplasm induces oil red O stain-positive lipid droplets. In gene
array studies, genes characteristic of sebaceous glands and those
involved in lipid and steroid metabolism were expressed in
SEB-1 sebocytes. The results by Thiboutot and colleagues
con¢rm the ¢ndings by Zouboulis et al (1999) that human
At their ¢rst studies on the physiology and pathophysiology of
the skin looking for an adequate ¢eld of future dedication, budding skin researchers usually go quickly through the chapter on
the Biology of Sebaceous Glands having obtained the following
piece of knowledge: sebaceous glands produce sebum and are
partially responsible for acne vulgaris. Seemingly, a limited and
less attractive ¢eld to work in, as Albert M. Kligman already
pointed out in 1963 with his statement ‘‘The sebaceous gland is a
living fossil with a past but not future,’’ in Montagna’s Advances
in Biology of the Skin.
Therefore, it may be of major importance for dermatological
research that a small number of dedicated researchers have made
a silent revolution during the last two decades by revising the
role of the sebaceous gland in human skin. This skin appendage
has turned to be an organelle with major involvement in skin
homeostasis, since sebaceous lipid fractions have been shown to
be responsible for the three-dimensional organization of the skin
surface lipids and the integrity of the skin barrier (Pilgram et al,
2001; Fluhr et al in press), and sebum was found to transport antioxidants to the skin surface (Thiele et al, 1999). In addition, sebaceous platelet-activating factor acetylhydrolase II was found to
protect the skin against oxidative stress and, especially, epidermal
keratinocytes against ultaviolet B irradiation (Marques et al, 2002),
the sebum-speci¢c lipids (C16 : 1D6) to exhibit innate antimicrobial activity (Ge et al, in press; Wille and Kydonieus, in press),
and sebocytes to express pro- and anti-in£ammatory properties
(Zouboulis et al, 1998; B˛hm et al, 2002; Toyoda et al, 2002; Wro¤bel
et al, 2003), to present a regulatory program for neuropeptides
(Zouboulis et al, 2002), and to control selectively the action of
hormones and xenobiotics on the skin (Akamatsu et al, 1992;
Tsukada et al, 2000). Several further sebaceous gland functions
are currently under investigation (Zouboulis et al, 1998; Chen
et al, in press) How much has changed since 1963!
In this issue, Thiboutot and colleagues put another milestone
to the sebaceous revolution. Based on previous knowledge that
sebaceous glands are capable of synthesizing cholesterol de novo
from acetate (Cassidy et al, 1986), they investigated whether the
skin, and especially the sebaceous gland, is capable of utilizing
cholesterol as a substrate for steroidogenesis. Cholesterol is used
in cell membrane construction and is a lipid fraction of sebum,
but its utilization by the skin as a substrate for steroidogenesis
would ful¢ll an important requirement for the skin function as
an independent peripheral endocrine organ (Zouboulis, 2000).
In order for steroid synthesis to occur, cholesterol needs to be
translocated from the outer root to the inner mitochondrial
membrane and consequently to be converted into pregnenolone
via the P450 side chain cleavage enzyme in concert with its cofactors adrenodoxin, adrenodoxin reductase, and the transcription
factor steroidogenic factor-1. Pregnenolone is converted to 17hydroxypregnenolone via 17a-hydrolase and to the androgen
precursor dehydroepiandrosterone by 17,20-lyase. 17a-Hydrolase
and 17,20-lyase activities are catalyzed by P450c17. Thiboutot and
0022-202X/03/$15.00 Copyright r 2003 by The Society for Investigative Dermatology, Inc.
xiv
VOL. 120, NO. 6 JUNE 2003
SEBACEOUS GLAND IN HUMAN SKIN
immortalized sebocytes transfected with Simian Virus- 40 large
T antigen possess normal sebocyte properties despite their
immortalization. An explanation for this ¢nding could be the
progressed stage speci¢c epithelial di¡erentiation of the parental
normal sebocytes which may hinder di¡erentiation of the cells
following their transfection.
Immortalized human facial sebaceous gland cell lines contribute signi¢cantly to the ongoing revision of the role of the
human sebaceous gland towards a major contributor in skin
homeostasis. Moreover, they will markedly assist the continuous
advancement in our understanding of skin endocrinology as
well as the intensi¢cation of investigations on the involvement
of the sebaceous gland in skin diseases. The sebaceous gland and
the research on it have a fantastic future!
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