IL-1β Stimulates Activin βA mRNA Expression in Human Skin Fibroblasts Through the MAPK Pathways, the Nuclear Factor-κB Pathway, and Prostaglandin E2

During mouse skin wound healing, mRNAs encoding IL-1, activins, and TGF-beta s significantly increased. To elucidate involvement of IL-1 in the regulation of activins and related factors in the wounded skin, human foreskin fibroblasts were stimulated with IL-1 beta, and levels of mRNAs encoding activins, TGF-beta s, and follistatin family proteins were examined by quantitative real-time PCR. IL-1 beta increased activin beta A (INHBA) and follistatin (FST) mRNA expression within 6 h. A p38 MAPK inhibitor, SB202190, a MAPK/ERK kinase inhibitor, U0126, and an nuclear factor kappa B pathway inhibitor, SC-514, significantly suppressed the IL-1 beta-stimulated INHBA and FST mRNA expression. A prostaglandin-endoperoxide synthase inhibitor indomethacin, a potent inhibitor of prostaglandin E-2 (PGE(2)) synthesis, also significantly suppressed the IL-1 beta-stimulated INHBA but not FST mRNA expression. Furthermore, stimulation of fibroblasts with PGE(2) significantly increased INHBA mRNA. The PGE2-induced INHBA mRNA expression was significantly suppressed by U0126 and a protein kinase C inhibitor, Go 6983. Although IL-1 beta stimulated FST mRNA in an acute phase, long-term exposure of fibroblasts to IL-1 beta revealed time-dependent stimulatory and inhibitory effects of IL-1 beta on FST mRNA expression. On the other hand, coculture with keratinocytes significantly increased INHBA mRNA expression in dermal equivalents. In summary, the present study indicates that the p38 MAPK, the MAPK/ERK kinase, the nuclear factor kappa B pathway, and PGE2 mediate the effects of IL-1 beta on INHBA mRNA expression. Furthermore, it is indicated that keratinocyte-derived factor of factors stimulate INHBA mRNA expression during wound healing. (Endocrinology 152: 3779-3790, 2011)