Sebaceous Glands and the Prostaglandin Pathway—Key Stones of ...

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Sebaceous Glands and the Prostaglandin Pathway—Key Stones
of an Exciting Mosaic
Christos C. Zouboulis
Department of Dermatology, Charité Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
Prostaglandins (PG) are detected in virtually all organs and
cells, whereas their enhanced release follows inflammatory
mechanisms. PG synthesis, especially of PGE 2 , PGD 2 and
PGF 2a , also takes place in epidermal keratinocytes as a
result of arachidonic acid (AA) metabolism (Kondoh et al,
1985; Pentland and Needleman, 1986) and is differentially
supported by specific enzymatic systems, the constitutively
expressed cyclooxygenase (COX)-1 and the inducible COX-
2 (Holtzman et al, 1994). Several mediators, such as phorbol
myristate acetate, calcium ionophore A23187, melittin,
bradykinin, epidermal growth factor, 1-oleoyl-2-acetyl glycerol
platelet-activating factor (synthetic analog of diacylglycerol),
cholecalciferol, interleukin-1, and tumor growth
factor-a have been shown to activate this pathway (Kondoh
et al, 1985; Fairley et al, 1986; Kvedar and Levine, 1987;
Fisher et al, 1989; Pentland and Mahoney, 1990; Hanke
et al, 1996; Kanekura et al, 1998). Exogenous PG regulate
major keratinocyte functions, i.e., inhibit or stimulate proliferation
in vitro under different culture conditions (Harper,
1976; Sugita et al, 1986), modify cyclic nucleotide levels
(Wilkinson and Orenberg, 1979), and enhance calcium-induced
cornification (Evans et al, 1993). Endogenous PG
have been shown to enhance keratinocyte proliferation
(Pentland and Needleman, 1986). On the other hand, fibroblasts
are less responsive to PG pathway activators,
whereas keratinocytes can activate fibroblasts to produce
prostocyclin which is a paracrine prodifferentiating agent for
keratinocytes (Baden et al, 1992).
Despite the abundant knowledge on the PG pathway in
keratinocytes, little is known on its activity in sebaceous
gland cells, which represent differentiated epithelial cells.
PG synthesis, especially that of PGD 2 and PGE 2 , has been
detected in mouse sebaceous gland cells (Henke et al,
1986). In 1998, Ma et al reported a major finding: estrogen
treatment, which induces peroxisome proliferation in the
uropygial gland in the duck, also enhanced AA metabolism
in this organ. Conversion of PGD 2 to the natural PGJ 2 metabolite,
D 12 -PGJ 2 , was induced by estradiol treatment preceding
peroxisome proliferation. Exogenous D 12 -PGJ 2 and
15-deoxy-D 12,14 -PGJ 2 activated the peroxisome proliferators-activated
receptor (PPAR)-g1, being, therefore, its natural
ligands. On the other hand, Neufang et al (2001) have
shown that in a COX-2 overexpressing mouse, PG accumulation
occurs, the skin exhibits a preneoplastic phenotype,
and that sebaceous gland hyperplasia, increased
sebum levels, sparse coat of greasy hair, and hyperplasia of
scale epidermis due to a disturbed program of epidermal
differentiation are present. These data confirmed previous
results by Rosenfield et al (1998) that PPAR-g1 ligands induce
lipid accumulation in mouse preputial gland cells
in vitro. In addition, the latter group has shown that exogenous
carbaprostacyclin (cPGI 2 ), stable prostocyclin analogue and
a natural PPAR-d/-a ligand, significantly induced lipid-forming
colonies in mouse preputial gland cells in vitro and that
retinoid X receptor agonists amplified the effect of cPGI 2
(Kim et al, 2001). Proliferation of the mouse preputial gland
cells was also enhanced significantly by cPGI 2 . Interestingly,
AA induces accumulation of lipids in human sebaceous
gland cells in vitro (Wróbel et al, 2003) and downregulation
PPAR-a through selective ligands has currently been suggested
to be involved in the development of seborrhea and
acne (Zouboulis et al, 2003, 2005).
In this issue, Iwata et al (2005) close the knowledge gap
by providing evidence that 15-deoxy-D 12,14 -PGJ 2 augments
the formation of lipid droplets in hamster auricle sebaceous
gland cells in vitro. This effect occurs due to a diacylglycerol
acyltransferase-triggered increase of triacylglycerol synthesis,
which indicates sebaceous gland cell differentiation,
and is accompanied by an increase of the relative levels
of 15-deoxy-D 12,14 -PGJ 2 to PGF 2a and PGE 2 . Hamster auricle
sebaceous gland cells were found to constitutively
produce COX-2 but not COX-1, whereas human facial sebaceous
gland cells constitutively produce both COX-2
and COX-1 (Alestas et al, in press). Although COX inhibition
by indomethacin, diclofenac or NS-398 led to an expected
reduction of PGF 2a and PGE 2 production, synthesis
of 15-deoxy-D 12,14 -PGJ 2 increased, and triacylglycerol synthesis
was also enhanced. Triacylglycerol synthesis was
also enhanced in the presence of the PPAR-g1 ligand troglitazone.
Similarly, topical administration of indomethacin to
hamster auricles was found to cause the development of
sebaceous glands with the augmentation of sebum deposition
in vivo. The indomethacim and NS-398-augmented
15-deoxy-D 12,14 -PGJ 2 production and triacylglycerol synthesis
here suppressed by a nonselective cytochrome
P-450 inhibitor, which did not affect the similar troglitazone
effect.
This fascinating work provides a number of links in understanding
the biological role of the PG pathway in sebaceous
gland cells: a) COX-2 and a still unknown cytochrome
P-450 enzyme—downstream to PGD synthase—exhibit opposite
effects. Therefore, COX-2 inhibitors reduce PGF 2a
Copyright r 2005 by The Society for Investigative Dermatology, Inc.
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125 : 5 NOVEMBER 2005
SEBACEOUS AND PROSTAGLANDIN—MOSAIC
xi
and PGE 2 levels but increase 15-deoxy-D 12,14 -PGJ 2 production
and triacylglycerol synthesis. The clinical consequence
could be that COX-2 inhibition may lead to a
downregulation of an existing inflammatory reaction but
may also enhance seborrhoea; and b) both natural and
synthetic PPAR-g1 ligands enhance lipid synthesis in sebaceous
gland cells following different modes of action, which
for the natural PPAR-g1 ligand 15-deoxy-D 12,14 -PGJ 2 is the
regulation of a cytochrome P-450 enzyme.
In addition, the results of this study combined with the
results of the previous reports mentioned above give a partial
explanation of the rather complex sebotropic effect of estrogens
(Callens et al, 1996; Dieudonne et al, 2000). Estrogens
seem to upregulate 15-deoxy-D 12,14 -PGJ 2 synthesis and subsequently
enhance PPAR-g1 activity and sebaceous lipid synthesis
(Ma et al, 1998; Iwata et al, 2005). This pathway of
estrogen effectiveness is probably complementary to estrogen’s
capacity to upregulate the insulin-like growth factor-1
pathway and, subsequently, production of sebaceous lipids
(Makrantonaki et al, 2002; Mendez-Davila et al, 2004).
At last, the work of Iwata et al (2005) provides indirect
evidence that the inhibition of the lipoxygenase pathway,
which exhibits proinflammatory and sebotropic activities
and a possible regulation of PPAR-a (Alestas et al, in press;
Zouboulis et al, 2003, 2005) is likely to be more powerful
than the inhibition of the PG pathway, including PPAR-g1
regulation, for future treatments of seborrhea and acne. On
the other hand, manipulating the PG pathway may be of
great interest in improving the activity of aging sebaceous
glands by parallel downregulation of inflammatory signals,
thus improving the quality of aging skin.
DOI: 10.1111/j.0022-202X.2005.23922.x
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