期刊
NATURE IMMUNOLOGY
卷 16, 期 4, 页码 354-365出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3103
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资金
- National Health and Medical Research Council [1012353, 1043845, 1022144]
- National Heart Foundation of Australia [100480]
- Monash University (Larkins Fellowship)
- MIMR-PHI (Star Recruitment Fellowship)
- Australian Research Council [DP110103616]
- US National Institutes of Health [AI-15614, AR-45584, CA-04 6934]
- Deutsche Forschungsgemeinschaft [Bu 1222/3-3]
- American Heart Association [12Post12030134]
- Victorian Government's Operational Infrastructure Support Program
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.
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