Ihn Hironobu, Yamane Kenichi, Tamaki Kunihiko
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
J Invest Dermatol. 2005 Aug;125(2):247-55. doi: 10.1111/j.0022-202X.2005.23766.x.
Transforming growth factor-beta (TGF-beta) stimulates the transcription of the alpha2(I) collagen gene. The dermal fibroblast activation in systemic sclerosis (SSc) may be a result of stimulation by autocrine TGF-beta. In this study, we investigated whether p38 mitogen-activated protein kinase (MAPK) is involved in TGF-beta-induced transcriptional activation of the human alpha2(I) collagen gene in normal dermal fibroblasts and in upregulated extracellular matrix (ECM) expression in SSc fibroblasts. Type I collagen expression induced by TGF-beta was suppressed by the specific p38 MAPK inhibitors SB203580 or SB202190 in normal fibroblasts. TGF-beta induced phosphorylation and activation of p38 MAPK in normal dermal fibroblasts. Transient transfection of dominant-negative mutant p38 MAPK into normal fibroblasts abolished TGF-beta-induced promoter activity of the human alpha2(I) collagen gene in normal fibroblasts. Moreover, constitutive phosphorylation and activation of p38 MAPK was demonstrated in SSc fibroblasts, and the inhibition of p38 MAPK using specific p38 MAPK inhibitors or dominant-negative mutant p38 MAPK abolished the upregulated expression of type I collagen or fibronectin in SSc fibroblasts. These results strongly suggest the contribution of p38 MAPK signaling to the TGF-beta-mediated regulation of the human alpha2(I) collagen gene in normal dermal fibroblasts and constitutive upregulated expression of type I collagen and fibronectin in SSc fibroblasts.
转化生长因子-β（TGF-β）可刺激α2（I）型胶原基因的转录。系统性硬化症（SSc）中真皮成纤维细胞的激活可能是自分泌TGF-β刺激的结果。在本研究中，我们调查了p38丝裂原活化蛋白激酶（MAPK）是否参与TGF-β诱导的正常人真皮成纤维细胞中人类α2（I）型胶原基因的转录激活以及SSc成纤维细胞中细胞外基质（ECM）表达上调。在正常人成纤维细胞中，TGF-β诱导的I型胶原表达被特异性p38 MAPK抑制剂SB203580或SB202190抑制。TGF-β可诱导正常人真皮成纤维细胞中p38 MAPK的磷酸化和激活。将显性负性突变型p38 MAPK瞬时转染入正常人成纤维细胞可消除TGF-β诱导的正常人成纤维细胞中人类α2（I）型胶原基因的启动子活性。此外，在SSc成纤维细胞中证实了p38 MAPK的组成型磷酸化和激活，使用特异性p38 MAPK抑制剂或显性负性突变型p38 MAPK抑制p38 MAPK可消除SSc成纤维细胞中I型胶原或纤连蛋白的上调表达。这些结果强烈提示p38 MAPK信号通路在正常人真皮成纤维细胞中对TGF-β介导的人类α2（I）型胶原基因调控以及SSc成纤维细胞中I型胶原和纤连蛋白组成型上调表达中的作用。
