Journal Article

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

Hong, Jaewoo, Fujita, Mayumi, Barber, Kristina, Neff, C. Preston, Mantovani, Alberto, Li, Suzhao, Kim, Soohyun, Azam, Tania, Palmer, Brent E., Garlanda, Cecilia, Luo, Yuchun, Dinarello, Charles Anthony

2015

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: 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