IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction
IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction
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DOI：
10.1038/ni.3103
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发表时间：
2015-04-01
影响因子：
30.5
通讯作者：
Nold, Marcel F.
中科院分区：
文献类型：
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作者：
Nold-Petry, Claudia A.;Lo, Camden Y.;Nold, Marcel F.
白细胞介素37（IL-37）和IL-1 R8（SIGIRR或TIR 8）分别是IL-1配体家族和IL-1受体家族的抗炎孤儿成员。在这里，我们证明了内源性配体-受体复合物IL-37-IL-1 R8-IL-18 R α的形成和功能。三重复合物迅速组装在外周血单个核细胞的表面上的刺激后，与脂多糖。IL-1 R8或IL-18 R α的沉默损害了IL-37的抗炎活性。而具有完整IL-1 R8的IL-37转基因表达的小鼠（IL-37 tg小鼠）受到保护免于内毒素血症，IL-1 R8缺陷的IL-37 tg小鼠则没有。蛋白质组学和转录组学研究显示，IL-37利用IL-1 R8来利用信号分子Mer、PTEN、STAT 3和p62（dok）的抗炎特性，并抑制激酶Fyn和TAK 1和转录因子NF-κ B以及促分裂原活化蛋白激酶。此外，IL-37-IL-1 R8对代谢检查点激酶mTOR产生假饥饿效应。因此，IL-37与IL-18 R α结合，并利用IL-1 R8激活多方面的细胞内抗炎程序。
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.