title: Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8.
abstract: Similar to IL-1α and IL-33, IL-1 family member IL-37b translocates to the nucleus and is associated with suppression of innate and adaptive immunity. Here we demonstrate an extracellular function of the IL-37 precursor and a processed form. Recombinant IL-37 precursor reduced LPS-induced IL-6 by 50% (P < 0.001) in highly inflammatory human blood-derived M1 differentiated macrophages derived from selective subjects but not M2 macrophages. In contrast, a neutralizing monoclonal anti-IL-37 increased LPS-induced IL-6, TNFα and IL-1β (P < 0.01). The suppression by IL-37 was consistently observed at low picomolar but not nanomolar concentrations. Whereas LPS induced a 12-fold increase in TNFα mRNA, IL-37 pretreatment decreased the expression to only 3-fold over background (P < 0.01). Mechanistically, LPS-induced p38 and pERK were reduced by IL-37. Recombinant IL-37 bound to the immobilized ligand binding α-chain of the IL-18 receptor as well as to the decoy receptor IL-1R8. In M1 macrophages, LPS increased the surface expression of IL-1R8. Compared with human blood monocytes, resting M1 cells express more surface IL-1R8 as well as total IL-1R8; there was a 16-fold increase in IL-1R8 mRNA levels when pretreated with IL-37. IL-37 reduced LPS-induced TNFα and IL-6 by 50-55% in mouse bone marrow-derived dendritic cells, but not in dendritic cells derived from IL-1R8-deficient mice. In mice subjected to systemic LPS-induced inflammation, pretreatment with IL-37 reduced circulating and organ cytokine levels. Thus, in addition to a nuclear function, IL-37 acts as an extracellular cytokine by binding to the IL-18 receptor but using the IL-1R8 for its anti-inflammatory properties.
authors: Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
authors: Suzhao
authors: S
authors: Li
authors: Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
authors: C Preston
authors: CP
authors: Neff
authors: Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
authors: Kristina
authors: K
authors: Barber
authors: Laboratory of Cytokine Immunology, Konkuk University, 143-701 Seoul, Republic of Korea;
authors: Jaewoo
authors: J
authors: Hong
authors: Department of Dermatology, University of Colorado Denver, Aurora, CO 80045;
authors: Yuchun
authors: Y
authors: Luo
authors: Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
authors: Tania
authors: T
authors: Azam
authors: Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
authors: Brent E
authors: BE
authors: Palmer
authors: Department of Dermatology, University of Colorado Denver, Aurora, CO 80045;
authors: Mayumi
authors: M
authors: Fujita
authors: Research Institute Humanitas, 20089 Milan, Italy; and.
authors: Cecilia
authors: C
authors: Garlanda
authors: Research Institute Humanitas, 20089 Milan, Italy; and.
authors: Alberto
authors: A
authors: Mantovani
authors: Laboratory of Cytokine Immunology, Konkuk University, 143-701 Seoul, Republic of Korea;
authors: Soohyun
authors: S
authors: Kim
authors: Department of Medicine, University of Colorado Denver, Aurora, CO 80045; Department of Medicine, Radboud University Medical Centre, HB6500 Nijmegen, The Netherlands cdinare333@aol.com.
authors: Charles Anthony
authors: CA
authors: Dinarello
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019446:Endotoxemia / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000737:chemistry; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D055767:Immobilized Proteins / Q000378:metabolism; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D007375:Interleukin-1 / Q000737:chemistry* / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D009500:Neutralization Tests; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D055767:Immobilized Proteins; D007375:Interleukin-1; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C508587:IL37 protein, human; C546891:SIGIRR protein, human; C484529:SIGIRR protein, mouse
keywords: endotoxemia; immunity; inflammasome
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