Increased expression of TGF-β receptors by scleroderma fibroblasts:: Evidence for contribution of autocrine TGF-β signaling to scleroderma phenotype
Increased expression of TGF-β receptors by scleroderma fibroblasts:: Evidence for contribution of autocrine TGF-β signaling to scleroderma phenotype
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DOI：
10.1046/j.1523-1747.1998.00073.x
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发表时间：
1998-01-01
影响因子：
6.5
通讯作者：
Trojanowska, M
中科院分区：
文献类型：
--
作者：
Kawakami, T;Ihn, H;Trojanowska, M
硬皮病成纤维细胞与健康皮肤成纤维细胞相比表现出许多表型差异。这些差异中的一些，特别是I型胶原蛋白和其他细胞外基质蛋白的过表达，与转化生长因子-β（TGF-β）对真皮成纤维细胞的作用平行，表明硬皮病成纤维细胞表型可能由自分泌TGF-β信号传导的激活引起。为了验证这一假设，我们检测了TGF-β I型和II型受体在调节I型胶原转录中的作用。我们已经表明，在真皮成纤维细胞的瞬时转染测定中，I型或II型受体的过表达显著（3-4倍）增加α 2（I）胶原启动子活性。加入抗TGF-β抗体消除了受体过表达对胶原启动子活性的刺激作用，而加入纤溶酶增强了这种作用，表明这种作用依赖于自分泌TGF-β。此外，这些共转染实验表明TGF-β受体的表达水平是TGF-β自分泌调节I型胶原转录的限制因素。硬皮病和正常成纤维细胞中TGF-β受体I型和II型mRA表达水平的比较表明硬皮病细胞中两种受体类型的表达升高（2倍），这与TGF-β结合的增加相关。显著地，升高的TGF-β受体水平与升高的α 2（I）胶原mRNA水平相关。这些结果表明，硬皮病成纤维细胞I型胶原的产生增加是由于TGF-β受体的过表达。
Scleroderma fibroblasts exhibit numerous phenotypic differences when compared with healthy skin fibroblasts. Some of these differences, in particular overexpression of collagen type I and other extracellular matrix proteins, parallel the effect of transforming growth factor-beta (TGF-beta) on dermal fibroblasts, suggesting that the scleroderma fibroblast phenotype may result from activation of autocrine TGF-beta signaling. To test this hypothesis we examined the role of TGF-beta Type I and Type II receptors in regulating collagen type I transcription, We have shown that overexpression of either Type I or Type II receptors significantly (3-4-fold) increases alpha 2 (I) collagen promoter activity in transient transfection assays in dermal fibroblasts. Addition of anti-TGF-beta antibody abolished, whereas addition of plasmin enhanced, the stimulatory effect of receptor overexpression on collagen promoter activity, suggesting that this effect depends on autocrine TGF-beta, Moreover, these cotransfection experiments indicated that expression levels of TGF-beta receptors is a limiting factor in the autocrine regulation of collagen type I transcription by TGF-beta. Comparison of the TGF-beta receptor Type I and Type II mRA expression levels in scleroderma and normal fibroblasts have indicated elevated expression (2-fold) of both receptor types in scleroderma cells, which correlated with increased binding of TGF-beta. Significantly, elevated TGF-beta receptor levels correlated with elevated alpha 2 (I) collagen mRNA levels. These results suggest that the elevated production of collagen type I by scleroderma fibroblasts results from overexpression of TGF-beta receptors.