转录因子KLF4对滑膜成纤维细胞炎症介质表达的调控及其在类风湿关节炎发病中的作用

Krüppel-like factors（KLF4）is a pleiotropic transcription factor with diverse biological functions. Although the involvement of KLF4 in the regulation of inflammatory response has been studied in the recent studies, the expression profile and pathological role of KLF in the various chronic joint inflammatory disorders (e.g. rheumatoid arthritis (RA)) have not been reported at the moment. On the basis of our previous studies, TNF-α-treated fibroblast-like synoviocytes (FLSs) RA model will be established to investigate the expressions profiles and the DNA combining activity of KLF4 in RA. Moreover, we are going to modulate KLF4 expression levels in FLSs by employing techniques of genetic transfection and RNA interference (enhanced and repressed, respectively), so as to observe the effects of KLF4 on the expression of inflammatory cytokines in FLSs and to suggest the possible regulatory mechanism according to the transcriptional levels. Subsequently, KLF4 knockdown in the synovial tissue will be carried out via intra-articular injection of KLF4 siRNA-carrying plasmid vector on collagen (type II) induced arthritis (CIA) rats models, and the effects of KLF4 on the synovial inflammation, bone damage and inflammatory cytokine expression will be observed. The present study is designed to reveal the critical roles and the underlying mechanisms of KLF4 in the regulation of inflammatory mediators in RA FLSs, as KLF4 is believed to be a potent therapeutic target in the treatment of RA.

KLF4是一种具有多种生物学功能的转录因子。近年来研究发现KLF4在炎症反应调节中起重要作用，但其在类风湿关节炎（RA）等慢性关节炎症性疾病中的表达及病理意义尚未见报道。本项目拟在前期研究基础上，以TNF-α刺激的RA滑膜成纤维细胞为模型，观察KLF4在RA炎症中的表达和DNA结合活性改变；并采用基因转染和RNA干扰技术分别增强或减弱KLF4的表达，深入探讨KLF4对滑膜成纤维细胞炎症介质表达的影响，并从转录水平探讨其调控机制。进一步以胶原诱导的关节炎大鼠为RA动物模型，通过关节腔注射KLF4 siRNA表达载体抑制关节局部KLF4基因表达，分析KLF4在关节炎大鼠滑膜炎症、骨质破坏及炎症介质表达中的作用。本研究可望揭示KLF4对RA滑膜炎症介质表达的调控及机制，为类风湿关节炎的防治提供新的思路与实验线索。

KLF4是一种具有多种生物学功能的转录因子，其在炎症反应调节中起重要作用，但在类风湿关节炎（RA）中的表达及病理意义尚不清楚。本项目体外实验研究发现TNF-a能诱导滑膜细胞KLF4基因表达上调和活性改变。采用基因转染和RNA干扰技术，我们发现KLF4调节滑膜成纤维细胞中IL-6、iNOS等炎症介质表达。此外，KLF4不仅能结合和诱导这些炎症介质基因启动子的活性，而且能与NF-kB相互作用共同促进炎症介质基因的表达。通过关节腔注射KLF4 siRNA表达载体，我们发现KLF4基因沉默能缓解胶原性关节炎滑膜炎症、骨质破坏和降低炎症介质的表达。我们的研究从整体、细胞和分子水平揭示KLF4对RA滑膜炎症介质表达的调控作用及其机制，为类风湿关节炎的防治提供新的思路与实验线索。