Role for nuclear interleukin-37 in the suppression of innate immunity
The IL-1 family member IL-37 broadly suppresses innate inflammation and acquired immunity. Similar to IL-1α and IL-33, IL-37 is a dual-function cytokine in that IL-37 translocates to the nucleus but also transmits a signal via surface membrane receptors. The role of nuclear IL-37 remains unknown on...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 10; pp. 4456 - 4461 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
05.03.2019
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Subjects | |
Online Access | Get full text |
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Summary: | The IL-1 family member IL-37 broadly suppresses innate inflammation and acquired immunity. Similar to IL-1α and IL-33, IL-37 is a dual-function cytokine in that IL-37 translocates to the nucleus but also transmits a signal via surface membrane receptors. The role of nuclear IL-37 remains unknown on the ability of this cytokine to inhibit innate inflammation. Here, we compared suppression of innate inflammation in transgenic mice expressing native human IL-37 (IL-37Tg) with those of transgenic mice carrying the mutation of aspartic acid (D) to alanine (A) at amino acid 20 (IL-37D20ATg). The mutation D20A prevents cleavage of caspase-1, a step required for IL-37 nuclear translocation. In vitro, peritoneal macrophages from IL-37Tg mice reduced LPS-induced IL-1β, IL-6, TNFα and IFNγ by 40–50% whereas in macrophages from IL-37D20ATg mice this suppression was not observed, consistent with loss of nuclear function. Compared with macrophages from IL-37Tg mice, significantly less or no suppression of LPS-induced MAP kinase and NFκB activation was also observed in macrophages from IL-37D20ATg mice. In vivo, levels of IL-1β, IL-6, and TNFα in the lungs and liver were markedly reduced during endotoxemia in IL-37Tg mice but not observed in IL-37D20ATg mice. However, suppression of innate inflammation remains intact in the IL-37D20A mice once the cytokine is released from the cell and binds to its receptor. These studies reveal a nuclear function for suppression of innate inflammation and are consistent with the dual function of IL-37 and a role for caspase-1 in limiting inflammation. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewers: D.B., Institute of Protein Biochemistry; and T.C.T., Tufts University School of Medicine. Contributed by Charles A. Dinarello, January 3, 2019 (sent for review December 13, 2018; reviewed by Diana Boraschi and Theoharis C. Theoharides) Author contributions: S.L., J.A.-A., R.L.-V., and C.A.D. designed research; S.L., J.A.-A., C.P.N., I.W.T., T.A., P.B., and C.A.D. performed research; S.L., C.P.N., B.E.P., P.B., and C.A.D. contributed new reagents/analytic tools; S.L., J.A.-A., C.P.N., R.L.-V., and C.A.D. analyzed data; and S.L. and C.A.D. wrote the paper. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1821111116 |