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IL-37 is a fundamental inhibitor of innate immunity

Abstract

The function of interleukin 37 (IL-37; formerly IL-1 family member 7) has remained elusive. Expression of IL-37 in macrophages or epithelial cells almost completely suppressed production of pro-inflammatory cytokines, whereas the abundance of these cytokines increased with silencing of endogenous IL-37 in human blood cells. Anti-inflammatory cytokines were unaffected. Mice with transgenic expression of IL-37 were protected from lipopolysaccharide-induced shock, and showed markedly improved lung and kidney function and reduced liver damage after treatment with lipopolysaccharide. Transgenic mice had lower concentrations of circulating and tissue cytokines (72–95% less) than wild-type mice and showed less dendritic cell activation. IL-37 interacted intracellularly with Smad3 and IL-37-expressing cells and transgenic mice showed less cytokine suppression when endogenous Smad3 was depleted. IL-37 thus emerges as a natural suppressor of innate inflammatory and immune responses.

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Figure 1: Production and silencing of endogenous IL-37 in human PBMCs.
Figure 2: Effect of TLR-induced IL-37b on cytokine production in RAW cells.
Figure 3: Cytokine production in THP-1 and A549 cells transfected with the pIRES-IL-37b plasmid or mock-transfected with pIRES lacking IL-37b.
Figure 4: Smad3 and IL-37.
Figure 5: Amelioration of endotoxic shock in mice transgenic for IL-37b.
Figure 6: Production of LPS-induced cytokines in IL-37tg mice.
Figure 7: Cytokines and DC activation in IL-37tg and neg-WT spleens and whole blood.
Figure 8: Silencing of Smad3 reduces the activity of IL-37 in vivo.

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Acknowledgements

We thank F. Gamboni-Robertson and F. Eckerdt (both University of Colorado, Denver) for advice on immunofluorescence; T. Azam, T. Goncharov (both University of Colorado, Denver) and M. Fink (Ludwig-Maximilians University Munich) for assistance; L. Joosten (Radboud University Nijmegen) for performing immunohistochemistry; D. Finkel (R&D Systems) for assistance regarding the protein arrays; and P. Pagel (University of Technology Munich) for database research for IL-37-interacting molecules. Supported by the US National Institutes of Health (AI-15614 and CA-04 6934 to C.A.D.) and the Deutsche Forschungsgemeinschaft (747/1-1 to M.F.N. and Bu 1222/3-1, 3-2 and 3-3 to P.B.).

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M.F.N., C.A.N.-P., P.B. and C.A.D. designed the study, analyzed the data and wrote the manuscript. M.F.N., C.A.N.-P., J.A.Z. and P.B. did experiments. B.E.P. was in charge of the flow-cytometry analysis.

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Correspondence to Charles A Dinarello.

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Nold, M., Nold-Petry, C., Zepp, J. et al. IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol 11, 1014–1022 (2010). https://doi.org/10.1038/ni.1944

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