ZT55选择性抑制JAK-STAT通路抗类风湿性关节炎作用及其分子机制

Signaling pathways mediating the transduction of information between cells are essential for development, cellular differentiation and homeostasis. Their dysregulation is also frequently associated with human disease. The JAKs are cytoplasmic tyrosine kinases critical for intracellular signal transduction of many cytokines, growth factors, and hormones. The JAK-STAT pathway is critical for meeting the diverse challenges faced by the immune system. Small molecule inhibitors of JAK1 have been developed to target diseases with aberrant production of inflammatory cytokines. In particular, the use of a JAK-selective inhibitor has been shown to be effective in reducing symptoms in multiple rodent models of arthritis. Our previous studies had found that ZT55, isolated from Tripterygium wilfordii Hook.f, demonstrated significant activates on anti-arthritis and immune regulation. The exact mechanism of regulation remains unclear, despite its known function of the inhibition of STAT1 phosphorylation and the disruption of T cell differentiation. Thus, the work of clarification ZT55 systemic ways of action are of extreme important, including the characters of its selective manners on JAK-STAT pathways, the pattern of its action on upstream or downstream molecules, the influence of its modulatory activities on T cell directed differentiation and its regulatory activities on FLS cells. Furthermore, we’d like to further validate its therapeutic effects on various kinds of arthritis animal model. The research has great implications for understanding which JAK/STAT pathway is correlated under certain kind of autoimmune disease status and how JAK/STAT pathways work in rheumatoid arthritis，which may contribute a lot in discovering a new type of selective inhibitor of JAK-STAT pathways to cure autoimmune disease.

选择性和精确调控某一失衡的JAK-STAT信号通路对于自身免疫性疾病的机制探讨和新药发现至关重要。我们前期的研究发现来源于雷公藤的全新二萜类化合物ZT55具有很好的抗关节炎和免疫调控作用，进一步发现其可能是通过选择性抑制STAT1的磷酸化和阻断T细胞的增殖发挥作用，但确切机制尚不明确。本项目拟深入探讨ZT55作用于JAK-STAT通路的选择性和特点，通过对该通路上下游信号分子的作用方式、对T细胞分化为Th1、Th2和Th17的影响、及对FLS细胞活化的调控入手，明确其抑制JAK-STAT通路活化的作用位点和选择性调控特点；同时在关节炎动物模型进一步证实其药效和作用机理，从而阐明其选择性调控JAK-STAT通路发挥抗炎作用的确切机制。本研究对于认识JAK-STAT通路在类风湿性关节炎中的调控方式和选择性特点、以及发现药效肯定的选择性抑制JAK-STAT通路的小分子药物具有十分重要的意义。

JAK是一种非受体型酪氨酸激酶，目前的研究发现JAK-STAT信号通路几乎在所有的细胞因子信号传递中都发挥着重要作用，所以JAK被认为是治疗自身免疫性疾病的重要靶点，目前已有多个JAK抑制剂进入临床。我们的研究发现来源于雷公藤的全新二萜类化合物ZT55具有很好的抗关节炎和免疫调控作用，雷公藤作为中国传统医学中一种中草药，已有700多年的历史，其最主要的药理活性即是抗炎、抗肿瘤和免疫抑制作用。进一步发现ZT55可能是通过选择性抑制JAK1的磷酸化和阻断T细胞的增殖发挥作用，但确切机制尚不明确。本项目研究显示ZT55可以非选择性的作用于JAK激酶，而作用于JAK1/2亚型的强度明显大于JAK3亚型，从而抑制JAK-STAT通路的活性发挥抗炎作用，进一步抑制T细胞向Th1和Th17分化。深入的研究显示ZT55可以抑制巨噬细胞向M1型转化，而巨噬细胞的极化依赖于JAK-STAT信号通路的活化。ZT55对CIA类风湿性关节炎小鼠模型有明确的治疗作用，同时在整体水平进一步证明了ZT55对T细胞分化的抑制和对巨噬细胞极化的调控作用。本研究结果阐明了ZT55靶向作用于JAK激酶，抑制JAK-STAT信号通路的活性，从而抑制了T细胞的分化和调控巨噬细胞的极化而发挥抗类风湿性关节炎的作用。