Corticotropin-releasing hormone: An autocrine hormone that promotes lipogenesis in human sebocytes

Abstract

Sebaceous glands may be involved in a pathway conceptually similar to that of the hypothalamic-pituitary-adrenal (HPA) axis. Such a pathway has been described and may occur in human skin and lately in the sebaceous glands because they express neuropeptide receptors. Corticotropin-releasing hormone (CRH) is the most proximal element of the HPA axis, and it acts as central coordinator for neuroendocrine and behavioral responses to stress. To further examine the probability of an HPA equivalent pathway, we investigated the expression of CRH, CRH-binding protein (CRH-BP), and CRH receptors (CRH-R) in SZ95 sebocytes in vitro and their regulation by CRH and several other hormones. CRH, CRH-BP, CRH-R1, and CRH-R2 were detectable in SZ95 sebocytes at the mRNA and protein levels: CRH-R1 was the predominant type (CRH-R1͞CRH-R2 ‫؍‬ 2). CRH was biologically active on human sebocytes: it induced biphasic increase in synthesis of sebaceous lipids with a maximum stimulation at 10 ؊7 M and up-regulated mRNA levels of 3␤-hydroxysteroid dehydrogenase͞⌬ 5-4 isomerase, although it did not affect cell viability, cell proliferation, or IL-1␤-induced IL-8 release. CRH, dehydroepiandrosterone, and 17␤-estradiol did not modulate CRH-R expression, whereas testosterone at 10 ؊7 M down-regulated CRH-R1 and CRH-R2 mRNA expression at 6 to 24 h, and growth hormone (GH) switched CRH-R1 mRNA expression to CRH-R2 at 24 h. Based on these findings, CRH may be an autocrine hormone for human sebocytes that exerts homeostatic lipogenic activity, whereas testosterone and growth hormone induce CRH negative feedback. The findings implicate CRH in the clinical development of acne, seborrhea, androgenetic alopecia, skin aging, xerosis, and other skin disorders associated with alterations in lipid formation of sebaceous origin.

Differential expression of HPA axis homolog in the skin

“…Receptors for POMC peptides-Several key skin cell populations express the functional, cognate receptors activated by the above neuropeptides Luger et al, 1999;Slominski et al, 2004b;Slominski and Wortsman, 2000;Slominski et al, 2000d;Zouboulis et al, 2002). Specifically, MCR1, 2 and 5, as well as receptors for β-endorphin have been identified in human and rodent skin cells (Slominski et al, 2004b;Slominski et al, 2000d).…”

“…Mediators of this axis, i.e., CRH, urocortin and POMC peptides, would then regulate skin pigmentary, immune, epidermal, dermal and adnexal systems Ito et al, 2005;Kauser et al, 2006;Slominski, 2005;Slominski et al, 2004b;Slominski and Wortsman, 2000;Slominski et al, 1999c;Zbytek et al, 2004;Zouboulis et al, 2002). Accordingly, exposure to, for example, UV light (physical stress), or biological or chemical stress, would activate pathways involved in the local production of CRH and CRH related peptides and POMC-derived peptides (Slominski et al, 1996b;Slominski et al, 2004b;Slominski and Wortsman, 2000;Slominski et al, 1999c;Zbytek et al, 2006).…”

An update on the role of the sebaceous gland in the pathogenesis of acne

“…In addition, CRH significantly induces sebaceous lipids production, IL-6 and -8 synthesis and may upregulate mRNA levels of 3β-hydroxysteroid dehydrogenase/Δ 5-4 isomerase. 59,60 In acneinvolved skin the complete CRH system is abundant especially in the sebaceous glands (Fig. 3), possibly activating pathways which affect immune and inflammatory processes leading to the development and stress-induced exacerbation of acne.…”

Age‐specific hormonal decline is accompanied by transcriptional changes in human sebocytes in vitro

“…Immunocytochemistry was performed as previously described (Zouboulis et al, 2002). The preparations were incubated with the antibodies at dilutions 1 : 25 (ERα, ERβ), 1 : 50 (AR), 1 : 100 (GHR, IGF-IR, IR) for 30 min.…”

“…After 48 h treatment of SZ95 sebocytes with hormones at the concentrations mentioned above, Nile red microassay was performed as previously described (Zouboulis et al, 2002) using 485-nm excitation and 565-nm emission filters for neutral lipids and 540-nm excitation and 620-nm emission filters for polar lipids. Experiments were performed in triplicate, with 10 wells evaluated for each data point in each experiment.…”