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

被引：401

作者：

Nold-Petry, Claudia A. ^{[1
,2
]}

Lo, Camden Y. ^{[1
,3
]}

Rudloff, Ina ^{[1
,2
]}

Elgass, Kirstin D. ^{[3
]}

Li, Suzhao ^{[4
]}

Gantier, Michael P. ^{[5
,6
]}

Lotz-Havla, Amelie S. ^{[7
]}

Gersting, Soren W. ^{[7
]}

Cho, Steven X. ^{[1
,2
]}

Lao, Jason C. ^{[1
,2
]}

Ellisdon, Andrew M. ^{[8
,9
]}

Rotter, Bjoern ^{[10
]}

Azam, Tania ^{[4
]}

Mangan, Niamh E. ^{[11
]}

Rossello, Fernando J. ^{[12
]}

Whisstock, James C. ^{[8
,9
]}

Bufler, Philip ^{[13
]}

Garlanda, Cecilia ^{[14
]}

Mantovani, Alberto ^{[14
,15
]}

Dinarello, Charles A. ^{[4
,16
]}

Nold, Marcel F. ^{[1
,2
,4
]}

机构：

[1] MIMR PHI Inst Med Res, Ritchie Ctr, Melbourne, Vic, Australia

[2] Monash Univ, Dept Paediat, Melbourne, Vic 3004, Australia

[3] Monash Univ, Monash Micro Imaging, Melbourne, Vic 3004, Australia

[4] Univ Colorado Denver, Dept Med, Aurora, CO USA

[5] MIMR PHI Inst Med Res, Ctr Canc Res, Melbourne, Vic, Australia

[6] Monash Univ, Dept Mol & Translat Sci, Melbourne, Vic 3004, Australia

[7] Univ Munich, Mol Pediat, Munich, Germany

[8] Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3004, Australia

[9] Monash Univ, Australian Res Council Ctr Excellence Adv Mol Ima, Melbourne, Vic 3004, Australia

[10] GenXPro, Frankfurt, Germany

[11] MIMR PHI Inst Med Res, Ctr Innate Immun & Infect Dis, Melbourne, Vic, Australia

[12] Monash Univ, Victorian Bioinformat Consortium, Melbourne, Vic 3004, Australia

[13] Univ Munich, Dr von Hauner Childrens Hosp, Dept Pediat, Munich, Germany

[14] Humanitas Clin & Res Ctr, Rozzano, Italy

[15] Humanitas Univ, Rozzano, Italy

[16] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands

来源：

NATURE IMMUNOLOGY | 2015年 / 16卷 / 04期

基金：

英国医学研究理事会; 美国国家卫生研究院; 澳大利亚研究理事会;

关键词：

FAMILY-MEMBER; NEGATIVE REGULATOR; TOLL; INFLAMMATION; CELLS; EXPRESSION; INHIBITOR; TIR8/SIGIRR; MOLECULES; INFECTION;

D O I：

10.1038/ni.3103

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

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.

引用

页码：354 / 365

页数：12

共 46 条

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