McWhirter A, Colosetti P, Rubin K, Miyazono K, Black C
Rheumatology Unit, Royal Free Hospital, London, UK.
Lab Invest. 1994 Dec;71(6):885-94.
The ability of transforming growth factor-beta (TGF-beta) to induce synthesis of extracellular matrix proteins stimulated this study in which we address the hypothesis that TGF-beta can induce, in normal fibroblasts, the sustained, elevated collagen synthesis characteristic of the scleroderma fibroblast.
Fibroblasts were studied for synthesis of and responsiveness to TGF-beta. Secreted TGF-beta levels were determined in a bioassay and at the transcriptional level in a series of scleroderma (SSc) and normal fibroblasts. The ability of cells to interact functionally with a 3-dimensional collagen matrix after TGF-beta treatment was examined. The kinetics of TGF-beta-induced fibrosis in fibroblasts was studied.
SSc fibroblasts were not characterized by elevated TGF-beta synthesis. There was no evidence of coordinate regulation of TGF-beta and collagen over passage number. Repeated pulses of 200 pM of TGF-beta did not significantly induce sustained procollagen alpha 1(I) mRNA synthesis in normal fibroblasts, and this treatment did not significantly alter the characteristics of normal fibroblasts in a collagen gel. mRNA for both collagen and TGF-beta type II receptor was induced by TGF-beta in both SSc and control cells. SSc fibroblasts were found to have an impaired ability to activate the small latent complex of TGF-beta.
Our data give no support to the hypothesis that TGF-beta can maintain the SSc phenotype in vitro or that it is able to induce this phenotype. The inducibility of TGF-beta receptor mRNA in SSc fibroblasts after exposure to TGF-beta suggests that the lack of sustained elevation in collagen synthesis is not due to lack of responsiveness by the fibroblasts but is rather a reflection of the transient nature of TGF-beta-induced fibrosis.
转化生长因子-β（TGF-β）诱导细胞外基质蛋白合成的能力激发了本研究，在此研究中我们探讨了TGF-β可在正常成纤维细胞中诱导硬皮病成纤维细胞特有的持续、升高的胶原蛋白合成这一假说。
研究成纤维细胞对TGF-β的合成及反应性。通过生物测定法和转录水平测定一系列硬皮病（SSc）和成纤维细胞中分泌的TGF-β水平。检测TGF-β处理后细胞与三维胶原基质功能相互作用的能力。研究TGF-β诱导成纤维细胞纤维化的动力学。
SSc成纤维细胞的特征并非TGF-β合成增加。没有证据表明TGF-β和胶原蛋白在传代过程中有协同调节作用。200 pM的TGF-β重复脉冲未显著诱导正常成纤维细胞中前胶原α1（I）mRNA的持续合成，且该处理未显著改变正常成纤维细胞在胶原凝胶中的特性。TGF-β在SSc细胞和对照细胞中均诱导了胶原蛋白和II型TGF-β受体的mRNA表达。发现SSc成纤维细胞激活TGF-β小潜伏复合物的能力受损。
我们的数据不支持TGF-β可在体外维持SSc表型或能够诱导该表型这一假说。SSc成纤维细胞在暴露于TGF-β后TGF-β受体mRNA的可诱导性表明，胶原蛋白合成缺乏持续升高并非由于成纤维细胞缺乏反应性，而是反映了TGF-β诱导纤维化的短暂性质。
