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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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-03, Vol.116 (10), p.4456-4461
Main Authors: Li, Suzhao, Amo-Aparicio, Jesus, Neff, Charles P., Tengesdal, Isak W., Azam, Tania, Palmer, Brent E., López-Vales, Rubén, Bufler, Philip, Dinarello, Charles A.
Format: Article
Language:English
Subjects:
Alanine
Amino acids
Animals
Aspartic acid
Biological Sciences
Caspase
Caspase-1
Cell activation
Cell Nucleus - metabolism
Cytokines
Cytokines - metabolism
Endotoxemia
Female
IL-1β
Immunity
Immunity, Innate - genetics
Inflammation
Innate immunity
Interleukin 1
Interleukin 6
Interleukin-1 - genetics
Interleukin-1 - physiology
Lipopolysaccharides
Lipopolysaccharides - pharmacology
Liver
Lungs
Macrophages
Macrophages, Peritoneal - drug effects
Macrophages, Peritoneal - metabolism
Male
MAP kinase
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
NF-kappa B - metabolism
NF-κB protein
Nuclear transport
Peritoneum
Protein Transport
Receptors
Rodents
Transgenic animals
Transgenic mice
Translocation
Tumor necrosis factor-α
γ-Interferon
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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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1821111116