KGF-2通过IL6反式信号调控STAT3磷酸化抑制机械应力介导的增生性瘢痕研究

过度纤维增生导致的增生性瘢痕(HS)是烧伤及其他损伤后常见并发症，发病原因尚不清楚。病理性瘢痕的实质是成纤维细胞过度增殖及ECM的过度沉积。KGF-2具有显著抑制机械应力诱导疤痕形成的作用，但其抑制疤痕的分子机制尚且未知。RNA深度测序发现，KGF-2处理的HS成纤维细胞，IL-6和STAT3基因有显著改变。HS免疫荧光检测表明KGF-2下调pSTAT3和IL-6的表达。随后的Westernblot 证明，KGF-2减少HS中 p-STAT3的聚集。另外，我们观察到HS中存在高表达IL-6反式信号结合蛋白gp130。上述结果提示STAT3/IL-6反式信号在KGF-2调控的疤痕发展中具有重要作用。因此，本项目将深入研究KGF-2调控STAT3磷酸化的方式，确认KGF-2与IL-6反式信号及STAT3上游激酶在成纤维细胞增殖和ECM沉积中的作用，阐明KGF-2抑制机械应力介导疤痕的分子机制。

Exuberant fibroproliferation leading to hypertrophic scar (HS) is a common complication after burn and other injuries for reasons that are not well understood. The histological characteristic of HS is the hypercellularity due to increased numbers of fibroblasts and abnormal ECM deposition. Efficacy of KGF-2 on inhibiting mechanical stress-mediated scar formation is well known, however, the underlying mechanism by which KGF-2 regulates the fibroblasts proliferation and ECM deposition remains unclear. RNA-deep sequencing against the KGF-2-stimulated HS fibroblasts identified that the IL-6 and STAT3 pathway genes are significantly altered. HS showed decreased STAT3 phosphorylation and IL-6 over normal fibroblast (NF) after KGF-2 treatment by Immunofluorescence assay. Subsequent Western blot assay showed that treatment with KGF-2 also inhibited accumulation of p-STAT3. In addition, We observed that the cell surface signaling transducer glycoprotein 130，the binding protein of IL-6-trans-signaling is upregulated in HSF. Therefore, it suggests that the IL-6-trans-signaling-STAT3 pathway may play an important role in KGF-2 regulated HS pathogenesis. The objective of this project is to understand the regulatory mechanism of KGF-2-mediated STAT3 phosphorylation and IL-6 trans-signaling inteaction with STAT3 upstream kinase in fibroblast proliferation and ECM deposition.