类风湿性关节炎（RA）易复发及致残率高，目前尚缺有效的治疗手段。我们首次发现烟曲霉文丙衍生物（FC-99）具有抗RA作用。有趣的是，我们预实验的结果表明，当FC-99处理激活的巨噬细胞时，miR let-7 表达明显升高，而 IL-6表达降低；体内实验也表明FC-99可缓解炎症性组织损伤。可是，FC-99是如何通过miR let-7调控其靶基因发挥抗RA作用的机制不明。故我们推测：FC-99通过上调miR let-7的表达靶向IL-6基因，从而抑制IL-6与 PI3K/AKT和NF-κB信号通路之间的反馈活化而发挥其抗RA作用。本研究拟利用多种小鼠实验性关节炎模型及RA患者滑膜样本，评价FC-99抗RA的效果；采用干扰和过表达技术进行体内外试验，分析FC-99对巨噬细胞IL-6表达与PI3K/Akt及NFκB活性变化的相关性及其作用机制。本研究的完成将为研发抗RA新药提供重要依据。

Rheumatoid arthritis (RA) is a disease characterized by chronic inflammation of the joint, mediated by persistent synthesis of proinflammatory cytokines and matrix metalloproteinases, which leading to progressive destruction of cartilage and bone. About 1% of the adult population worldwide occurs RA, and is believed to be responsible for significant morbidity and increased disability rate. Biological compounds that suppress the synthesis of key inflammatory cytokines, including IL-6 and TNF-α, are successful at treating RA in the short term. However, a relatively large subset of RA patients does not respond to these drugs and patients that initially respond well can become refractory over time. Thus it remains an unmet need for an economical mode of treatment that is efficacious over the long term..We first identified that a Fumigaclavine C (FC)-derivated new compound, FC-99, could effectively alleviate the inflammatory damages in adjuvant arthritis mice. And the microRNA regulating mechanisms is still lack of clarity. In our previous study, the expression of miR let-7 was significantly high in FC-treated activated macrophages, while IL-6 mRNA level is comparatively low. In two murine dis-inflammatory diseases models, FC-99 could strongly attenuate inflammation-mediated tissue injuries. Thus we prompt that FC-99 up-regulates miR let-7, targets IL-6 and regulates PI3K/AKT or NF-κB signaling, leading to protective effects on RA..To elucidate the roles, we continue the investigations: ① evaluate the activity of FC-99 on joint synovial tissues from RA patients, and examine the in vivo potential of FC-99 by evaluating its efficacy in various experimental murine RA models;② demonstrate whether the activity of FC-99 on RA is induced by miR let-7 targetting IL-6 both in vitro and in vivo; ③ investigate the action of FC-99 on PI3K/Akt and NF-κB signaling pathways to elucidate the molecular mechanisms involved. These results will suggest FC-99 is an attractive compound for the treatment of inflammation disorders such as RA.

类风湿性关节炎（RA）易复发及致残率高，目前尚缺有效的治疗手段。本研究在FC-99抑制巨噬细胞产生IL-6等炎性因子的基础上，基于多种免疫疾病小鼠模型，试图筛选并评价FC-99是否具有抗RA等免疫炎性损伤的治疗效果，并对其抗RA等机制进行深入研究。 本研究建立了高收率、低成本制备小分子化合物FC-99的方法；成功复制多种急慢性免疫性疾病的动物模型，鉴定了FC-99的治疗作用；探索了以巨噬细胞为核心的免疫调控评价方式；揭示了FC-99发挥抗炎作用的具体机制。（1）发现FC-99能够较好的阻断巨噬细胞产生炎性因子、抑制Th17细胞的分化，改善小鼠RA的症状。进一步揭示FC-99治疗RA的作用机制主要是通过促进巨噬细胞的miR-494产生，并使其负向调控TN-C在炎性部位的表达，进而调控RORγt抑制Th17细胞分化，发挥较强的促进RA小鼠免疫平衡的作用。（2）发现let-7a是FC-99调控巨噬细胞命运的关键分子，可较好的防止脓毒症小鼠肝功能衰竭。进一步揭示FC-99治疗肝损伤的作用机制主要是通过诱导单核细胞高表达let-7a，靶向抑制抗凋亡基因BCL-XL的表达，促进单核细胞凋亡，阻断单核/巨噬细胞分化，从而明显减少外周血中Ly6Chi炎性单核细胞亚群比例，促进肝脏内浸润单核细胞积累，减少其向F4/80lo巨噬细胞分化，发挥较强的抑制肝脏免疫炎性损伤的作用。（3）发现FC-99可有效阻断TLR/IRAK4/BAFF信号轴，明显抑制pDC细胞的表达和分泌IFN-α，大大减弱DCs细胞的活化，具有较强的改善MRL/lpr小鼠狼疮样症状的功能。（4）确认FC-99调控巨噬细胞TLR2/TLR4信号通路治疗DSS诱导的小鼠肠炎模型症状。（5）发现FC-99的类似物FC-98可通过抑制MyD88和TRIF依赖的信号通路明显改善CLP小鼠脓毒症损伤症状。本研究的完成将为研发抗RA新药提供重要依据。