STA-21，一种有前途的 STAT-3 抑制剂，可相互调节 Th17 和 Treg 细胞，抑制小鼠和人类的破骨细胞生成，并在类风湿关节炎的实验模型中缓解自身免疫炎症。
STA-21, a promising STAT-3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis.
机构信息
Catholic University of Korea, Seoul, South Korea.
出版信息
Arthritis Rheumatol. 2014 Apr;66(4):918-29. doi: 10.1002/art.38305.
OBJECTIVE
To investigate the impact of STA-21, a promising STAT-3 inhibitor, on the development and progression of inflammatory arthritis and to determine the possible mechanisms by which STA-21 has antiarthritic effects in interleukin-1 receptor antagonist-knockout (IL-1Ra-KO) mice, an animal model of rheumatoid arthritis (RA).
METHODS
IL-1Ra-KO mice were treated with intraperitoneal injections of STA-21 (0.5 mg/kg) or vehicle 3 times per week for 3 weeks. The mouse joints were assessed for clinical and histologic features of inflammatory arthritis. CD4+CD25+FoxP3+ Treg cells and CD4+IL-17+ cells were defined. Human peripheral blood mononuclear cell-derived monocytes or mouse bone marrow-derived monocyte/macrophage (BMM) cells were cultured in the presence of macrophage colony-stimulating factor alone or together with RANKL and various concentrations of STA-21, followed by staining of the cells for tartrate-resistant acid phosphatase activity to determine osteoclast formation.
RESULTS
STA-21 suppressed inflammatory arthritis in IL-1Ra-KO mice. The proportion of Th17 cells was decreased and the proportion of Treg cells expressing FoxP3 was markedly increased in the spleens of STA-21-treated mice. Adoptive transfer of CD4+CD25+ T cells obtained from STA-21-treated IL-1Ra-KO mice markedly suppressed inflammatory arthritis. In vitro treatment with STA-21 induced the expression of FoxP3 and repressed IL-17 expression in both mouse and human CD4+ T cells. Moreover, STA-21 prevented both mouse BMM cells and human monocytes from differentiating into osteoclasts in vitro.
CONCLUSION
STA-21 improved the clinical course of arthritis in IL-1Ra-KO mice. It increased not only the number of Treg cells but also the function of the Treg cells. It also suppressed Th17 cells and osteoclast formation. These data suggest that STA-21 might be an effective treatment for patients with RA.
目的
研究 STAT-3 抑制剂 STA-21 对炎症性关节炎发展和进展的影响，并确定 STA-21 在白细胞介素-1 受体拮抗剂敲除（IL-1Ra-KO）小鼠（类风湿关节炎（RA）的动物模型）中具有抗关节炎作用的可能机制。
方法
每周 3 次通过腹腔内注射 STA-21（0.5mg/kg）或载体处理 IL-1Ra-KO 小鼠 3 周。评估小鼠关节的炎症性关节炎临床和组织学特征。定义 CD4+CD25+FoxP3+Treg 细胞和 CD4+IL-17+细胞。在单独存在或与 RANKL 和各种浓度的 STA-21 一起培养人外周血单核细胞衍生的单核细胞或鼠骨髓衍生的单核细胞/巨噬细胞（BMM）细胞后，对细胞进行抗酒石酸酸性磷酸酶染色以确定破骨细胞形成。
结果
STA-21 抑制了 IL-1Ra-KO 小鼠的炎症性关节炎。STA-21 处理的小鼠脾脏中 Th17 细胞的比例降低，表达 FoxP3 的 Treg 细胞的比例明显增加。从 STA-21 处理的 IL-1Ra-KO 小鼠中获得的 CD4+CD25+T 细胞的过继转移显着抑制了炎症性关节炎。STA-21 体外处理诱导了小鼠和人 CD4+T 细胞中 FoxP3 的表达并抑制了 IL-17 的表达。此外，STA-21 可防止体外的鼠 BMM 细胞和人单核细胞分化为破骨细胞。
结论
STA-21 改善了 IL-1Ra-KO 小鼠关节炎的临床病程。它不仅增加了 Treg 细胞的数量，而且还增加了 Treg 细胞的功能。它还抑制了 Th17 细胞和破骨细胞的形成。这些数据表明 STA-21 可能是治疗 RA 患者的有效方法。
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