Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 8; pp. 2497 - 2502
• Main Authors: Li, Suzhao, Neff, C. Preston, Barber, Kristina, Hong, Jaewoo, Luo, Yuchun, Azam, Tania, Palmer, Brent E., Fujita, Mayumi, Garlanda, Cecilia, Mantovani, Alberto, Kim, Soohyun, Dinarello, Charles Anthony
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.02.2015; National Acad Sciences
• Subjects: Animals; Biological Sciences; Blood; Bone marrow; caspase-1; Cell Differentiation - drug effects; Cells; Cytokines; Endotoxemia - metabolism; Endotoxemia - pathology; Enzyme Activation - drug effects; Extracellular Space - chemistry; Flow Cytometry; Gene expression; Gene Expression Regulation - drug effects; Humans; Immobilized Proteins - metabolism; immunity; Immunity, Innate; inflammation; Inflammation - immunology; Inflammation - pathology; Interleukin-1 - chemistry; Interleukin-1 - metabolism; interleukin-1beta; Interleukin-1beta - metabolism; interleukin-6; Interleukin-6 - metabolism; Lipopolysaccharides - pharmacology; macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - enzymology; Macrophages - metabolism; Mice; Neutralization Tests; p38 Mitogen-Activated Protein Kinases - metabolism; Protein Structure, Tertiary; receptors; Receptors, Interleukin-1 - chemistry; Receptors, Interleukin-1 - metabolism; Recombinant Proteins - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - metabolism; inflammasome; endotoxemia; immunity
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1424626112

Significance Interleukin-1 family members are highly inflammatory but IL-37 member broadly suppresses inflammation and specific immunity. Initially, the mechanism of this suppression was shown to be via translocation to the nucleus following cleavage of the precursor by intracellular caspase-1. We now show that recombinant forms of IL-37 limit inflammation by extracellular binding to surface receptors but require the IL-1 family decoy receptor IL-1R8. Unexpectedly, picomolar concentrations of the IL-37 precursor optimally suppress IL-1β, IL-6, and TNFα production from human blood M1 macrophages, suggesting a unique function for a coreceptor function of IL-1R8. Assessment of IL-37 as well as IL-1R8 levels may provide previously unidentified insights into how the host limits inflammation. 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.