IL-17调节TGF-β1信号及其在肾间质纤维化中的意义

Inflammation is closely related to the process of fibrosis. Renal interstitial fibrosis is a common result of chronic kidney diseases and determines the status of renal function. Whether the inflammatory cytokine IL-17 is one of contributing factors to the renal interstitial fibrosis is not known. It’s reported that IL-17 can promote the fibrogenesis in myocardium, lung and liver. There is no demonstration of its role in Inflammation is closely related to the process of fibrosis. Renal interstitial fibrosis is a common result of chronic kidney diseases and determines the status of renal function. Whether the inflammatory cytokine IL-17 is one of contributing factors to the renal interstitial fibrosis is not known. It’s reported that IL-17 can promote the fibrogenesis in myocardium, lung and liver. There is no demonstration of its role in renal interstitial fibrosis, however. Previously we found that IL-17-/- mice displayed exacerbation of renal interstitial fibrosis induced by unilateral ureteric obstruction (UUO). IL-17 could inhibit the production of extra cellular matrix by myofibroblast in vitro. What mechanisms were involved in this inhibitory effect of IL-17 on renal interstitial fibrosis? We aim to demonstrate the TGF-β1 signaling in IL-17-/- mice after UUO surgery. Furthermore, signaling in IL-17 regulating TGF-β1-induced activation, proliferation and function of fibroblast will be analyzed by protein microarray and tested in the coming study in vivo. The findings in the present study will clarify the inhibitory role of IL-17 in the renal interstitial fibrosis. At the same time, the results can provide better understanding of regulatory effects of IL-17 on TGF-β1 signaling in fibrogenesis.

炎性细胞因子IL-17是否参与肾间质纤维化？文献提示IL-17可促进心肌、肺、肝等组织纤维化，未见与肾纤维化关系的相关报道。我们的预研显示，IL-17-/-鼠发生较野生型更为严重的肾间质纤维化；IL-17可抑制肌成纤维细胞合成细胞外基质。为什么IL-17-/-鼠的肾间质纤维化会加重？IL-17抑制肾间质纤维化的机制是什么？TGF-β1在肾间质纤维化中处于核心位置，本项目提出假设：IL-17通过干预TGF-β1的经典和/或非经典信号通路，制约TGF-β1的促纤维化作用。研究方案①分析IL-17-/-鼠发生肾间质纤维化其TGF-β1 经典和/或非经典信号分子的活化状态；②调查IL-17对TGF-β1所诱导的成纤维细胞的增殖、活化与合成细胞外基质的调节作用；蛋白质芯片筛选并确证该调节作用所涉及的关键信号分子。研究成果将从机制上阐明IL-17抑制肾间质纤维化的原因。

炎性细胞因子IL-17在其他组织器官的纤维化中具有一定作用，但其与肾间质纤维化的关系尚不明确。本研究通过在野生型C57/B6鼠及IL-17基因敲除型鼠构建UUO模型，取肾组织分析： HE染色、PAS染色、Masson染色、-SMA的表达水平、Ⅰ型胶原和纤连蛋白的聚集、炎性细胞因子（TNF-α、IL-1β、IL-6）以及IL-17和TGF-b1的表达水平，发现IL-17基因敲除鼠经UUO诱导后发生严重的肾间质纤维化病变，病变程度比野生型小鼠重，炎性细胞因子的表达水平也较高。体外研究IL-17对TGF-b1所诱导的成纤维细胞的增殖、活化与合成细胞外基质的调节作用及其胞内信号机制，IL-17对肾源性与非肾源性成纤维细胞转化为肌成纤维细胞及其表达细胞外基质的作用不同，IL-17抑制TGF-β诱导的肾脏成纤维细胞表达α-SMA, Type I Collagen及FN，其分子机制是IL-17降低TGF-β诱导的小鼠肾脏成纤维细胞的p38MAPK和Akt信号分子的磷酸化水平。体内实验进一步显示IL-17基因敲除鼠的梗阻肾脏组织中TGF-β相关的促纤维化信号分子p38MAPK and AKT 的磷酸化水平显著高于野生型小鼠。本研究的重要发现是：IL-17对肾间质纤维化起抑制作用，从理论上拓展IL-17在器官纤维化中的意义；更新对于IL-17的认识，它不仅是一种炎性细胞因子，同时还具有免疫调节功能。同时，IL-17对不同组织来源的成纤维细胞的作用特点提示IL-17的免疫调节作用可能具有组织选择性。IL-17能够抑制肾间质纤维化，还可以为临床控制此类疾病的病情发展提供新的治疗思路。