IL-35 ameliorates collagen-induced arthritis by promoting TNF--induced apoptosis of synovial fibroblasts and stimulating M2 macrophages polarization
IL-35 ameliorates collagen-induced arthritis by promoting TNF--induced apoptosis of synovial fibroblasts and stimulating M2 macrophages polarization
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IL-35 通过促进 TNF 诱导的滑膜成纤维细胞凋亡和刺激 M2 巨噬细胞极化来改善胶原诱导的关节炎
DOI：
10.1111/febs.14801
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发表时间：
2019-05-01
期刊：
影响因子：
5.4
通讯作者：
Wang, Jinwu
中科院分区：
文献类型：
--
作者：
Peng, Mingzheng;Qiang, Lei;Wang, Jinwu
滑膜炎是滑膜的慢性炎症，是类风湿性关节炎的标志，类风湿性关节炎是一种严重影响人类健康的慢性疾病。最近，白介素35(IL-35)作为IL-12家族的新成员，被发现是一种抗炎和免疫抑制的细胞因子，并被证明可以改善小鼠的胶原性关节炎。然而，IL-35减轻CIA的机制仍不清楚。在本研究中，我们研究了IL-35对CIA微环境的影响，特别是对肿瘤坏死因子-α(TNF-α)诱导的巨噬细胞炎症反应和成纤维细胞样滑膜细胞(Fls)凋亡的影响。首先，利用RT-PCR、Western印迹和流式细胞术，我们发现IL-35通过下调外周血单核细胞来源的巨噬细胞中iNOS和COX-2的表达来抑制肿瘤坏死因子诱导的炎症反应。根据对CCR7和CD206表达的评估，IL-35还激活了M2巨噬细胞的交替极化。此外，我们还发现IL-35增强了肿瘤坏死因子诱导的FLS细胞的凋亡。在18只DBA/1J小鼠建立的CIA模型中，利用一组免疫组织化学和免疫荧光分析，我们证明了IL-35促进滑膜细胞凋亡和巨噬细胞交替激活以减轻体内关节炎。综上所述，我们的结果表明，在体外和体内，IL-35促进了肿瘤坏死因子诱导的FLS的凋亡，并通过调节M2巨噬细胞的极化来减轻CIA的炎症。
Synovitis, the chronic inflammation of the synovial membranes, is a hallmark of rheumatoid arthritis, a chronic disease with profound impact on human health. Recently, interleukin-35 (IL-35), a new member of the IL-12 family, was identified as an anti-inflammatory and immunosuppressive cytokine and was shown to ameliorate collagen-induced arthritis (CIA) in mice. However, the mechanism by which IL-35 alleviates CIA remains unknown. In this study, we investigated the effect of IL-35 on the CIA microenvironment and, specifically, the tumor necrosis factor alpha (TNF-)-induced macrophage inflammatory response and apoptosis of fibroblast-like synoviocytes (FLSs). Firstly, using RT-PCR, western blot, and flow cytometry, we found that IL-35 suppressed TNF--induced inflammatory responses by down-regulating iNOS and COX-2 in peripheral blood monocyte-derived macrophages. IL-35 also activated alternative M2 macrophage polarization, as determined by evaluation of CCR7 and CD206 expression. Moreover, we showed that IL-35 enhanced TNF--induced FLS apoptosis. Using a panel of immunohistochemical and immunofluorescence analyses in a CIA model established in 18 DBA/1J mice, we demonstrated that IL-35 promotes synoviocyte apoptosis and alternative activation of macrophages to alleviate arthritis in vivo. Taken together, our results show that IL-35 promotes TNF--induced FLS apoptosis and modulates M2 macrophage polarization to ameliorate CIA inflammation both in vitro and in vivo.