IL-34对Th17细胞的调控在类风湿关节炎发病中的作用

Interleukin-17(IL-17) producing cells (Th17 cells) play a role in the pathogenesis of rheumatoid arthritis (RA). However, factors that drive Th17 cells differentiation are not well defined. IL-34 is a newly discovered cytokine without significant amino acid sequence homology to other cytokines or proteins. Study identifies IL-34 expression in the synovial tissue of patients with RA. A significant association was found between IL-34 expression and synovitis severity. Despite the overall effects observed in RA, the role of IL-34 in RA remains largely unclear. Our previous study showed that increased sera levels of IL-34 from patients with RA compared with control subjects. The IL-34 levels were correlated with disease activity. Following co stimulation with recombinant human (rh) IL-34 and anti-CD3/CD28, the amounts of IL-17 in supernatants from the CD4+T cells of patients with RA were significantly higher than those CD4+T cells stimulated with anti-CD3/CD28 alone. Taken together, this data suggest a role for IL-34 in pathogenesis of RA, which maybe induced by Th17 cells. To test this concept, we plan to study the effect of IL-34 on differentiation of Th17 cells and collagen-induced arthritis (CIA) development. Thus, it may offer novel therapeutic target for RA.

白细胞介素(Interleukin,IL)-34为新发现的细胞因子。IL-34对Th17细胞功能是否有影响以及是否参与类风湿关节炎(rheumatoid arthritis,RA)的发病及机制如何，目前没有相关报道。我们前期的研究发现RA患者外周血IL-34水平明显升高。体外培养RA患者的CD4+T细胞，加入IL-34后可明显增加IL-17表达。因此我们推测IL-34可能促进na?ve CD4+T向Th17细胞分化，并通过Th17细胞介导参与RA发病。为证实这一假设,我们以RA的动物模型-胶原诱导关节炎（CIA）为研究对象，采用分子生物学，siRNA，基因敲除，流式细胞检测及组织学等方法,通过离体与在体水平研究IL-34对Th17细胞的调控及在RA发病中的作用，揭示其对Th17细胞功能的影响及在CIA发病中的作用机制。本研究将为寻找RA的新靶向生物治疗提供理论依据,对RA的防治有重要意义。

白细胞介素（IL）-34是一种新发现的炎性细胞因子。免疫组化染色发现在类风湿关节炎（RA）患者的滑膜组织上有IL-34的表达。我们认为，它可能参与RA的发生和发展。本研究通过体外和体内实验观察IL-34与RA和胶原诱导型关节炎(CIA)的关系，探讨IL-34在RA发病中对炎症、骨质疏松及血管新生的影响，以及该作用是否通过对Th17细胞的调控来完成。. 我们的研究结果表明：IL-34可促进PBMC中Th17细胞的百分比及IL-17的分泌。同时IL-34可促进RORγt mRNA的表达，且均为浓度依赖性。通过在体研究发现IL-34可明显加重CIA发病，阻断IL-17后可削弱IL-34的作用。IL-34促进CIA鼠外周血中 TNF-α, IL-17和IL-6的分泌以及CIA鼠滑膜中 TNF-α, IL-17和IL-6的表达，阻断IL-17后TNF-α及IL-6的分泌及表达下降。RT-PCR及 western-blot法检测发现IL-34可促进CIA鼠滑膜组织中IL-17、TNF-αmRNA及蛋白的表达。通过离体研究发现IL-34可通过调控IL-17促进FLS的增殖，抑制其凋亡，且呈剂量依赖性。并可促进RA相关致病炎性因子（TNF-α，IL-6）的分泌与表达。IL-34可促进PBMC及FLS分泌破骨相关因子RANKL, 抑制OPG，从而促进RA骨破坏进程。而阻断IL-17之后，IL-34对RANKL表达的促进作用被抑制。通过体外实验发现IL-34对血管新生血管因子的分泌有影响：可促进VEGF、HIF的分泌，抑制FGF的分泌。阻断IL-34后观察发现CIA发病明显减轻，且炎性细胞因子IL-17，TNF-α，IL-6的分泌及表达被抑制。. 以上研究表明IL-34可促进CIA的发病，且可通过对IL-17的调控完成，从而为RA的发病机制研究以及治疗靶点提供新的思路。