Increased expression of integrin αvβ3 contributes to the establishment of autocrine TGF-β signaling in scleroderma fibroblasts
Increased expression of integrin αvβ3 contributes to the establishment of autocrine TGF-β signaling in scleroderma fibroblasts
复制标题
DOI：
10.4049/jimmunol.175.11.7708
复制
发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Tamaki, K
中科院分区：
文献类型：
--
作者：
Asano, Y;Ihn, H;Tamaki, K
培养物中许多细胞类型的潜伏TGF-β的组成性分泌表明，控制这种有效细胞因子活性的细胞外机制在可能涉及这种细胞因子的疾病（包括纤维化病症）的发病机制中是重要的。在这项研究中，我们集中在α（v）β（3）整合素，这是最近被证明作为一个活跃的受体，潜伏性TGF-β 1通过其与潜伏相关肽β 1的相互作用，并调查了这种整合素在硬皮病的发病机制的参与。硬皮病成纤维细胞表现出增加的a，p，表达与正常成纤维细胞相比，在体内和体外。在硬皮病成纤维细胞中，ERK通路被组成性激活，这种异常诱导α（v）β（3）的上调，在正常成纤维细胞中，α（v）β（3）的瞬时过表达诱导人α 2（1）胶原基因启动子活性的增加和人MMP-1基因启动子活性的降低。α 13的这些作用通过用抗TGF-β Ab或TGF-β 1反义寡核苷酸处理几乎完全消除。此外，抗-α，13，Ab的加入逆转了硬皮病成纤维细胞中I型前胶原蛋白和MMP-1蛋白的表达、人α 2（1）胶原基因的启动子活性以及成肌纤维细胞表型。这些结果表明，α 13的上调表达有助于在硬皮病成纤维细胞中建立自分泌TGF-β环，并且这种整联蛋白是治疗硬皮病的有效靶标。
The constitutive secretion of latent TGF-beta by many cell types in culture suggests that extracellular mechanisms to control the activity of this potent cytokine are important in the pathogenesis of the diseases in which this cytokine may be involved, including fibrotic disorders. In this study, we focused on the alpha(v)beta(3) integrin, which is recently demonstrated to function as an active receptor for latent TGF-beta 1 through its interaction with latency-associated peptide-beta 1, and investigated the involvement of this integrin in the pathogenesis of scleroderma. Scleroderma fibroblasts exhibited increased a,p, expression compared with normal fibroblasts in vivo and in vitro. In scleroderma fibroblasts, ERK pathway was constitutively activated and such abnormality induced the up-regulation of alpha(v)beta(3), Transient overexpression of a(v)beta(3), in normal fibroblasts induced the increase in the promoter activity of human alpha 2(1) collagen gene and the decrease in that of human MMP-1 gene. These effects of a,13, were almost completely abolished by the treatment with anti-TGF-beta Ab or TGF-beta 1 antisense oligonucleotide. Furthermore, the addition of anti-a,13, Ab reversed the expression of type I procollagen protein and MMP-1 protein, the promoter activity of human a2(1) collagen gene, and the myofibroblastic phenotype in scleroderma fibroblasts. These results suggest that the up-regulated expression of a,13, contributes to the establishment of autocrine TGF-beta loop in scleroderma fibroblasts, and this integrin is a potent target for the treatment of scleroderma.