Department of Surgical Sciences, Plastic Surgery Unit, Uppsala University, Uppsala, Sweden.
J Cell Biochem. 2010 Aug 1;110(5):1226-33. doi: 10.1002/jcb.22637.
Connective tissue growth factor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor (TGF)-beta and intimately involved with tissue repair and overexpressed in various fibrotic conditions. We previously showed that keratinocytes in vitro downregulate TGF-beta-induced expression of CTGF in fibroblasts by an interleukin (IL)-1 alpha-dependent mechanism. Here, we investigated further the mechanisms of this downregulation by both IL-1alpha and beta. Human dermal fibroblasts and NIH 3T3 cells were treated with IL-1alpha or beta in presence or absence of TGF-beta1. IL-1 suppressed basal and TGF-beta-induced CTGF mRNA and protein expression. IL-1alpha and beta inhibited TGF-beta-stimulated CTGF promoter activity, and the activity of a synthetic minimal promoter containing Smad 3-binding CAGA elements. Furthermore, IL-1alpha and beta inhibited TGF-beta-stimulated Smad 3 phosphorylation, possibly linked to an observed increase in Smad 7 mRNA expression. In addition, RNA interference suggested that TGF-beta activated kinase1 (TAK1) is necessary for IL-1 inhibition of TGF-beta-stimulated CTGF expression. These results add to the understanding of how the expression of CTGF in human dermal fibroblasts is regulated, which in turn may have implications for the pathogenesis of fibrotic conditions involving the skin.
结缔组织生长因子 (CTGF/CCN2) 是一种基质细胞蛋白，由转化生长因子 (TGF)-β诱导产生，与组织修复密切相关，并在各种纤维化条件下过度表达。我们之前的研究表明，体外角质形成细胞通过白细胞介素 (IL)-1α 依赖性机制下调成纤维细胞中 TGF-β诱导的 CTGF 表达。在这里，我们通过 IL-1α 和 β 进一步研究了这种下调的机制。用人真皮成纤维细胞和 NIH 3T3 细胞在存在或不存在 TGF-β1 的情况下用 IL-1α 或 β 处理。IL-1 抑制 CTGF 的基础和 TGF-β诱导的 mRNA 和蛋白表达。IL-1α 和 β 抑制 TGF-β 刺激的 CTGF 启动子活性和含有 Smad 3 结合 CAGA 元件的合成最小启动子的活性。此外，IL-1α 和 β 抑制 TGF-β 刺激的 Smad 3 磷酸化，这可能与观察到的 Smad 7 mRNA 表达增加有关。此外，RNA 干扰表明，TGF-β 激活激酶 1 (TAK1) 是 IL-1 抑制 TGF-β 刺激的 CTGF 表达所必需的。这些结果增加了对人真皮成纤维细胞中 CTGF 表达如何受到调节的理解，这反过来可能对涉及皮肤的纤维化疾病的发病机制具有重要意义。
