MASM诱导耐受型树突状细胞的机制及其治疗类风湿关节炎的作用研究

Tolerogenic dentritic cells (TDC) can induce T cell tolerance and suppress the development of autoimmune diseases such as rheumatoid arthritis. In our previous study, MASM has been shown to inhibit DC maturation and inhibit the collagen-induced arthritis in rats. Furthermore, MASM inhibits LPS-induced PI3K/Akt, MAPK and NFκB pathways and specifically binds to Raf kinase inhibitor protein (RKIP). RKIP has been reported to interact with Raf, NIK, TAK1 and IKK and negatively regulate the NFκB and ERK pathways. This project will validate effect of MASM on DC mature through RKIP. Furthermore, we will reveal its molecular mechanism that may be involved in the regulation of RKIP interaction with Raf, NIK, TAK1 and IKK, and subsequently affected the downstream transcriptional factor activities of NFκB and AP-1. In addition, MASM-treated DCs and Lenti-shRKIP-treated DCs were administered to mice with collagen-induced arthritis and their therapeutic effects and possible mechanism will be studied. Together，our results will reveal role of RKIP on DC mature and clarify the molecular mechanism of MASM for its inhibitory effect on DC mature and point to RKIP as a therapeutic target for rheumatoid arthritis.

耐受型DC具有诱导T细胞耐受而抑制自身免疫性疾病的作用。我们前期研究发现苦参碱衍生物MASM能抑制DC成熟和抑制II型胶原诱导的类风湿性关节炎，进一步研究发现MASM抑制NFκB、MAPK和PI3K/Akt的信号通路的活化且特异性结合Raf激酶抑制蛋白(RKIP)。文献报道RKIP与Raf、NIK 、TAK1、IKK相互作用负向调控ERK、NFκB通路。本项目拟应用RNA干扰技术确证MASM通过RKIP抑制DC成熟，并揭示RKIP通过调控Raf、NIK 、TAK1、IKK进而影响下游转录因子NFκB和AP-I的活性调控DC成熟的分子机制；研究MASM诱导的耐受型DC和RKIP敲减的DC的表型和功能及其治疗胶原诱导的小鼠关节炎的效果和机制。研究结果可揭示RKIP在DC成熟中的作用，深入阐明MASM抑制DC成熟的分子机制，明确MASM的作用靶点，为治疗自身性免疫疾病提供新靶点。