Interleukin-35 Inhibits TNF-α-Induced Osteoclastogenesis and Promotes Apoptosis via Shifting the Activation From TNF Receptor-Associated Death Domain (TRADD)-TRAF2 to TRADD-Fas-Associated Death Domain by JAK1/STAT1.
Interleukin-35 Inhibits TNF-α-Induced Osteoclastogenesis and Promotes Apoptosis via Shifting the Activation From TNF Receptor-Associated Death Domain (TRADD)-TRAF2 to TRADD-Fas-Associated Death Domain by JAK1/STAT1.
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Interleukin-35 通过 JAK1/STAT1 将激活从 TNF 受体相关死亡结构域 (TRADD)-TRAF2 转移到 TRADD-Fas 相关死亡结构域，抑制 TNF-α 诱导的破骨细胞生成并促进细胞凋亡
DOI：
10.3389/fimmu.2018.01417
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发表时间：
2018
影响因子：
7.3
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Peng M;Wang Y;Qiang L;Xu Y;Li C;Li T;Zhou X;Xiao M;Wang J
由骨髓或外周血单核细胞衍生的破骨细胞被炎性细胞因子过度激活导致骨质疏松症、骨关节炎和其他骨侵蚀相关疾病。白细胞介素35（IL-35）是一种新型的抗炎免疫抑制因子。本研究探讨了IL-35对TNF-α诱导的破骨细胞生成的影响。在IL-35的存在下，通过抗酒石酸酸性磷酸酶（TRAP）染色、F-肌动蛋白染色和骨吸收测定来检测该过程。通过TUNEL染色、细胞活力测定和流式细胞术证实IL-35对TNF-α诱导的细胞凋亡的影响。同时，采用基因芯片技术检测IL-35对TNF-α-activated phosphatase kinase的影响。进一步研究了IL-35对TNF-α介导的NF-κB、MAPK、TRAF 2、RIP 1、Fas相关死亡结构域（FADD）和caspase 3活化的影响。另外，通过将TNF-α皮下注射到小鼠颅骨上来建立小鼠颅骨溶解模型，随后进行组织学分析。结果表明，IL-35在体外抑制TNF-α诱导的破骨细胞形成和骨吸收，在体内抑制颅骨骨溶解。IL-35通过抑制NF-κB和MAPK下调NFATc 1、c-fos和TRAP表达，同时激活JAK 1/STAT 1。TUNEL染色和流式细胞仪检测显示IL-35可增强TNF-α诱导的破骨细胞凋亡。同时，TNF-α和IL-35处理的细胞中FADD和切割型caspase 3表达增加，NF-κB的DNA结合活性在TNF-α处理的细胞中增加，但在TNF-α和IL-35处理的细胞中降低。总之，IL-35通过激活JAK 1/STAT 1并将激活从TNF受体相关死亡结构域（TRADD）-TRAF 2/RIP 1-NF-κB转移到TRADD-FADD-caspase 3信号传导来抑制TNF-α诱导的破骨细胞生成并促进细胞凋亡。
Over-activated osteoclasts derived from myeloid or peripheral blood monocytes by inflammatory cytokines results in osteoporosis, osteoarthritis, and other bone erosion-related diseases. Interleukin 35 (IL-35) is a novel anti-inflammatory and immunosuppressive factor. This study investigated the effect of IL-35 on TNF-α-induced osteoclastogenesis. In the presence of IL-35, this process was detected by Tartrate-Resistant Acid Phosphatase (TRAP) staining, F-actin staining, and bone resorption assays. The effects of IL-35 on TNF-α-induced apoptosis were demonstrated by TUNEL staining, cell viability assays, and flow cytometry. Moreover, a microarray was performed to detect the effect of IL-35 on TNF-α-activated phosphatase kinase. The effect of IL-35 on the TNF-α-mediated activation of NF-κB, MAPK, TRAF2, RIP1, Fas-associated death domain (FADD), and caspase3 was further investigated. In addition, a murine calvarial osteolysis model was established via the subcutaneous injection of TNF-α onto the calvaria, and histological analysis was subsequently performed. As a result, IL-35 inhibited TNF-α-induced osteoclast formation and bone resorption in vitro and osteolysis calvaria in vivo. NFATc1, c-fos, and TRAP were downregulated by IL-35 through the inhibition of NF-κB and MAPK, during which JAK1/STAT1 was activated. Moreover, based on TUNEL staining and flow cytometry, IL-35 was shown to enhance TNF-α-induced osteoclast apoptosis. Meanwhile, FADD and cleaved-caspase 3 were increased in cells treated with TNF-α and IL-35, whereas the DNA-binding activity of NF-κB was increased in TNF-α-treated cells, but was decreased in cells treated with both TNF-α and IL-35. In conclusion, IL-35 inhibits TNF-α-induced osteoclastogenesis and promotes apoptosis by activating JAK1/STAT1 and shifting activation from TNF receptor-associated death domain (TRADD)-TRAF2/RIP1-NF-κB to TRADD-FADD-caspase 3 signaling.
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影响因子：
16.6
作者：
Dambuza IM;He C;Choi JK;Yu CR;Wang R;Mattapallil MJ;Wingfield PT;Caspi RR;Egwuagu CE
通讯作者：
Egwuagu CE
影响因子：
5.4
作者：
Chen, Li;Wei, Xiao-Qing;Aeschlimann, Daniel
通讯作者：
Aeschlimann, Daniel
影响因子：
4.4
作者：
Furukawa, Mitsuru;Takaishi, Hironari;Toyama, Yoshiaki
通讯作者：
Toyama, Yoshiaki
IL-35 预处理通过抑制 NF-κ B 激活减轻脂多糖诱导的小鼠急性肾损伤
影响因子：
5.1
作者：
Hu, Linkun;Chen, Cheng;Hou, Jianquan
通讯作者：
Hou, Jianquan
影响因子：
4.1
作者：
KANEHISA, J;YAMANAKA, T;TAKEUCHI, H
通讯作者：
TAKEUCHI, H