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Nat Immunol. 2015 Apr;16(4):354-65. doi: 10.1038/ni.3103. Epub 2015 Mar 2.

IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction.

Author information

1
1] Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Department of Paediatrics, Monash University, Melbourne, Australia.
2
1] Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Monash Micro Imaging, Monash University, Melbourne, Australia.
3
Monash Micro Imaging, Monash University, Melbourne, Australia.
4
Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
5
1] Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Department of Molecular and Translational Science, Monash University, Melbourne, Australia.
6
Molecular Pediatrics, Ludwig-Maximilians University, Munich, Germany.
7
1] Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia. [2] Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, Australia.
8
GenXPro, Frankfurt, Germany.
9
1] Department of Molecular and Translational Science, Monash University, Melbourne, Australia. [2] Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Melbourne, Australia.
10
Victorian Bioinformatics Consortium, Monash University, Melbourne, Australia.
11
Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany.
12
Humanitas Clinical and Research Center, Rozzano, Italy.
13
1] Humanitas Clinical and Research Center, Rozzano, Italy. [2] Humanitas University, Rozzano, Italy.
14
1] Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA. [2] Radboud University Medical Centre, Nijmegen, the Netherlands.
15
1] Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Department of Paediatrics, Monash University, Melbourne, Australia. [3] Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.

Abstract

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-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα 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-κB, 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-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.

PMID:
25729923
DOI:
10.1038/ni.3103
[Indexed for MEDLINE]

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