Involvement of αvβ5 integrin in the establishment of autocrine TGF-β signaling in dermal fibroblasts derived from localized scleroderma
Involvement of αvβ5 integrin in the establishment of autocrine TGF-β signaling in dermal fibroblasts derived from localized scleroderma
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DOI：
10.1038/sj.jid.5700331
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发表时间：
2006-08-01
影响因子：
6.5
通讯作者：
Tamaki, Kunihiko
中科院分区：
文献类型：
--
作者：
Asano, Yoshihide;Ihn, Hironobu;Tamaki, Kunihiko
局限性硬皮病（LSc）是一种局限于皮肤和皮下组织的结缔组织疾病，其可能与系统性硬化症（SSc）共享致病过程。我们先前证明整合素α v β 5的上调表达可能有助于SSc成纤维细胞自分泌TGF-β信号。基于这些数据，我们目前专注于α v β 5，并评估其参与LSc的发病机制。我们最初证明LSc成纤维细胞可能被自分泌TGF-β的刺激激活。与SSc成纤维细胞一致，在体外和体内LSc成纤维细胞中α v β 5的表达水平升高。抗α v β 5抗体部分逆转了LSc成纤维细胞中I型前胶原和MMP- 1的表达水平以及组成型DNA-Smad 3结合。在用反义TGF-β 1预处理的LSc成纤维细胞中，外源性潜伏性TGF- B 1刺激以α v β 5依赖性方式增加I型前胶原的表达。与正常成纤维细胞共培养相比，与LSc成纤维细胞共培养的TMLC细胞（稳定表达纤溶酶原激活物抑制剂1启动子的一部分的Mv 1 Lu细胞）的荧光素酶活性显著升高，并且在抗-a v B 5抗体存在下显著降低。抗α v β 5抗体逆转了LSc成纤维细胞的肌纤维母细胞特征。这些结果表明a v B 5的上调表达有助于LSc成纤维细胞中的自分泌TGF-β信号传导。
Localized scleroderma ( LSc) is a connective tissue disorder limited to skin and subcutaneous tissue, which may share pathogenic processes with systemic sclerosis ( SSc). We previously demonstrated that upregulated expression of integrin alpha v beta 5 might contribute to autocrine TGF-beta signaling in SSc fibroblasts. Based on these data, we presently focused on alpha v beta 5 and assessed its involvement in pathogenesis of LSc. We initially demonstrated that LSc fibroblasts might be activated by the stimulation of autocrine TGF-beta. Consistent with SSc fibroblasts, expression levels of alpha v beta 5 were elevated in LSc fibroblasts in vitro and in vivo. Anti- alpha v beta 5 antibody partially reversed expression levels of type I procollagen and MMP- 1 and constitutive DNA - Smad3 binding in LSc fibroblasts. In LSc fibroblasts pretreated with antisense TGF-b1, exogenous latent TGF- b 1 stimulation increased expression of type I procollagen in an alpha v beta 5- dependent manner. The luciferase activities of TMLC cells, Mv1Lu cells stably expressing a portion of the plasminogen activator inhibitor 1 promoter, co-cultured with LSc fibroblasts were significantly elevated compared with those co-cultured with normal fibroblasts and were significantly reduced in the presence of anti-a v b 5 antibody. Anti-alpha v beta 5 antibody reversed the myofibroblastic features of LSc fibroblasts. These results indicate that upregulated expression of a v b 5 contributes to autocrine TGF-beta signaling in LSc fibroblasts.