Smad-independent transforming growth factor-β regulation of early growth response-1 and sustained expression in fibrosis -: Implications for scleroderma
Smad-independent transforming growth factor-β regulation of early growth response-1 and sustained expression in fibrosis -: Implications for scleroderma
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DOI：
10.2353/ajpath.2008.080382
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发表时间：
2008-10-01
影响因子：
6
通讯作者：
Varga, John
中科院分区：
文献类型：
--
作者：
Bhattacharyya, Swati;Chen, Shu-Jen;Varga, John
转化生长因子-β(TGF-β)在硬皮病发病机制中起关键作用。转录因子早期生长反应-1(Egr-1)介导了转化生长因子-β对胶原转录的刺激作用，在小鼠肺纤维化的发生发展中起重要作用。在此，我们报道了转化生长因子-β通过血清反应元件引起正常成纤维细胞中Egr-1蛋白和mRNA水平的时间和剂量依赖性增加以及Egr-1基因转录的增强。转化生长因子-β刺激Egr-1的能力在Smad3基因缺失的小鼠和移植的Smad3基因缺失的成纤维细胞中得到保留。这种反应可被特定的有丝分裂原激活的蛋白激酶1(MEK1)抑制剂阻断，但不能被Alk5激酶抑制剂阻断。此外，MEK1被转化生长因子-β磷酸化，这足以驱动Egr-1反式激活。转化生长因子-β刺激通过MEK-细胞外信号调节激酶1/2途径增强E1K-1的转录活性。博莱霉素诱导的小鼠硬皮病伴随着皮损成纤维细胞中Egr-1的增加。此外，硬皮病患者的皮损皮肤和肺活检显示Egr-1水平升高，这在早期弥漫性疾病中最高。此外，在体外移植的硬皮病皮肤成纤维细胞中，Egr-1mRNA和蛋白均升高。总之，这些发现确定了一种Smad非依赖的转化生长因子-β信号转导机制，该机制是Egr-1刺激的基础，首次证明了Egr-1在纤维化病变中持续上调，并表明Egr-1在纤维化的诱导和发展中发挥了作用。
Transforming growth factor-beta (TGF-beta) plays it key role in scleroderma pathogenesis. The transcription factor early growth response-1 (Egr-1) mediates the stimulation of collagen transcription elicited by TGF-beta and is necessary for the development of pulmonary fibrosis in mice. Here, we report that TGF-beta causes a time- and dose-dependent increase in Egr-1 protein and mRNA levels and enhanced transcription of the Egr-1 gene via serum response elements in normal fibroblasts. The ability of TGF-beta to stimulate Egr-1 was preserved in Smad3-null mice and in explanted Smad3-null fibroblasts. The response wits blocked by a specific mitogen-activated protein kinase kinase 1 (MEK1) inhibitor but not by an ALK5 kinase inhibitor. Furthermore, MEK1 was phosphorylated by TGF-beta, which was sufficient to drive Egr-1 transactivation. Stimulation by TGF-beta enhanced the transcriptional activity of E1k-1 via the MEK-extracellular signal-regulated kinase 1/2 pathway. Bleomycin-induced scleroderma in the mouse was accompanied by increased Egr-1 accumulation in lesional fibroblasts. Furthermore, biopsies of lesional skin and lung from patients with scleroderma showed increased Egr-1 levels, which were highest in early diffuse disease. Moreover, both Egr-1 mRNA and protein were elevated in explanted scleroderma skin fibroblasts in vitro. Together, these findings define a Smad-independent TGF-beta signal transduction mechanism that underlies die stimulation of Egr-1, demonstrate for die first time sustained Egr-1 up-regulation in fibrotic lesions and suggests that Egr-1 has a role in the induction and progression of fibrosis.