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首页> 外文期刊>Nature immunology >IL-37 requires the receptors IL-18R alpha and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction
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IL-37 requires the receptors IL-18R alpha and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction

机译:IL-37需要受体IL-18R alpha和IL-1R8(SIGIRR)在先天信号转导时执行其多方面的抗炎程序

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摘要

Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18R alpha. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18R alpha impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-kappa B, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18R alpha and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.
机译:白介素37(IL-37)和IL-1R8(SIGIRR或TIR8)分别是IL-1配体家族和IL-1受体家族的消炎性孤儿。在这里,我们证明了内源性配体-受体复合物IL-37-IL-1R8-IL-18Rα的形成和功能。在用脂多糖刺激后,三方复合物在外周血单核细胞的表面迅速组装。 IL-1R8或IL-18Rα的沉默会削弱IL-37的抗炎活性。具有完整的IL-1R8的转基因表达IL-37的小鼠(IL-37tg小鼠)可以免受内毒素血症的侵害,而缺乏IL-1R8的IL-37tg小鼠则不受内毒素血症的侵害。蛋白质组学和转录组学研究表明,IL-37使用IL-1R8来利用信号分子Mer,PTEN,STAT3和p62(dok)的抗炎特性,并抑制Fyn和TAK1激酶以及转录因子NF-κB以及促分裂原激活的蛋白激酶。此外,IL-37-IL-1R8对代谢检查点激酶mTOR起假饥饿作用。因此,IL-37与IL-18Rα结合,并利用IL-1R8激活多方面的细胞内抗炎程序。

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