Effects of α-melanocyte stimulating hormone and 11ß-hydroxysteroid dehydrogenase type 1 on sebogenesis in SZ95 sebocytes
Dept. of Medical Science/박사
A causative link between psychological stress and acne has long been postulated. When the activity of the hypothalamic-pituitary-adrenal (HPA) axis system is increased due to stress, it results to the secretion of various hormones, such as the melanocortins and glucocorticoids. It is well known that α-melanocyte stimulating hormone (α-MSH) causes lipogenesis in cultured human sebocytes. Although corticosteroids cause immunosuppressive and anti-inflammatory effects, it is clinically well known that systemic or topical glucocorticoid treatment aggravates an acneiform reaction. The 11β-hydroxysteroid dehydrogenase type 1 (HSD11β1) regenerates active glucocorticoids from inactive forms and plays a central role in regulating intracellular glucocorticoid concentration. First of all, the effect of α-MSH was investigated on the expression of its receptors, MC1R and MC5R, according to the differentiated status of sebocytes and the expression of pro-inflammatory cytokines and toll-like receptor (TLR) 2. Additionally, different effects of α-MSH on the lipogenesis were investigated. Second, it was investigated whether HSD11β1 is expressed in sebocytes and cytokines affect on the expression of HSD11β1. Similarly, whether HSD11β1 affects sebogenesis on sebocytes was also investigated. Consequently, MC5R was only observed in differentiated SZ95 sebocytes. Lipid droplets were increased by α-MSH in differentiated SZ95 sebocytes. Moreover, SREBP-1c mRNA was increased by α-MSH, and SREBP-1c mRNA was more increased in differentiated SZ95 sebocytes. These results suggest that the sebotrophic effect of α-MSH in SZ95 sebocytes via MC5R is superior to that of the sebotrophic effect happening via MC1R. The IP3 receptor antagonist and the PLC inhibitor suppressed the expression of SREBP-1c mRNA which was induced by α-MSH in both undifferentiated and differentiated SZ95 sebocytes.
These results indicate that α- MSH induces sebogenesis in SZ95 sebocytes by induction of SREBP-1c via IP3/PLC pathway. The expression of HSD11β1 in SZ95 sebocytes was increased by dexamethasone. An increment of HSD11β1 expression was inhibited by RU-486, glucocorticoid receptor (GR) antagonist, PF-915275, HSD11β1 specific inhibitor, and pioglitazone, PPAR-γ agonist. Similarly, dexamethasone increased sebogenesis in SZ95 sebocytes. In addition, RU-486, PF-915275, and pioglitazone inhibited sebogenesis induced by dexamethasone in SZ95 sebocytes. Moreover, dexamethasone increased the expression of SREBP-1a and 1c mRNA. The increment of SREBP-1a and 1c mRNA expression was inhibited by RU486, PF-915275, and pioglitazone. These data demonstrate that HSD11β1 involves dexamethasone-induced lipid synthesis, which is induced by SREBP-1a and 1c via GR. α-MSH induced the gene expression level of pro-inflammatory cytokines, such as IL-1α, IL-6 and TNF-α in both undifferentiated and differentiated SZ95 sebocytes. IL-1α, IL-6 and TNF-α induced HSD11β1 gene expression level in SZ95 sebocytes and α-MSH induced TLR-2 gene expression in differentiated SZ95 sebocytes. Dexamethasone also induced TLR-2 gene expression in SZ95 sebocytes. These results suggest that α-MSH and dexamethasone may involve inflammatory and immune reaction in acne vulgaris lesions. To conclude, psychological stress induced α-MSH induced not only sebum secretion but also inflammation in acne vulgaris. Furthermore, the following findings suggest that receptors of α-MSH and HSD11β1 could be critical factors for the medical treatment of acne vulgaris.