title: IL-1beta stimulates activin betaA mRNA expression in human skin fibroblasts through the MAPK pathways, the nuclear factor-kappaB pathway, and prostaglandin E2.
abstract: During mouse skin wound healing, mRNAs encoding IL-1, activins, and TGF-βs 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-1β, and levels of mRNAs encoding activins, TGF-βs, and follistatin family proteins were examined by quantitative real-time PCR. IL-1β increased activin βA (INHBA) and follistatin (FST) mRNA expression within 6 h. A p38 MAPK inhibitor, SB202190, a MAPK/ERK kinase inhibitor, U0126, and an nuclear factor κB pathway inhibitor, SC-514, significantly suppressed the IL-1β-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-1β-stimulated INHBA but not FST mRNA expression. Furthermore, stimulation of fibroblasts with PGE(2) significantly increased INHBA mRNA. The PGE(2)-induced INHBA mRNA expression was significantly suppressed by U0126 and a protein kinase C inhibitor, Gö 6983. Although IL-1β stimulated FST mRNA in an acute phase, long-term exposure of fibroblasts to IL-1β revealed time-dependent stimulatory and inhibitory effects of IL-1β 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 κB pathway, and PGE(2) mediate the effects of IL-1β on INHBA mRNA expression. Furthermore, it is indicated that keratinocyte-derived factor of factors stimulate INHBA mRNA expression during wound healing.
authors.affiliation: Division of Matrix Biology, Scleroprotein Research Institute, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan. kojiarai@cc.tuat.ac.jp
authors.forename: Koji Y
authors.initials: KY
authors.lastname: Arai
authors.forename: Mariko
authors.initials: M
authors.lastname: Ono
authors.forename: Chikako
authors.initials: C
authors.lastname: Kudo
authors.forename: Atsuko
authors.initials: A
authors.lastname: Fujioka
authors.forename: Ryoko
authors.initials: R
authors.lastname: Okamura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nomura
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishiyama
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics; D015232:Dinoprostone / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D016762:Genes, fos; D028322:Inhibin-beta Subunits / Q000235:genetics*; D053583:Interleukin-1beta / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis*; D014945:Wound Healing
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; C103008:inhibin beta A subunit; D028322:Inhibin-beta Subunits; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D015232:Dinoprostone