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The nuclear cytokine IL-37a controls lethal cytokine storms primarily via IL-1R8-independent transcriptional upregulation of PPARγ.
- Source :
-
Cellular & molecular immunology [Cell Mol Immunol] 2023 Dec; Vol. 20 (12), pp. 1428-1444. Date of Electronic Publication: 2023 Oct 27. - Publication Year :
- 2023
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Abstract
- Cytokine storms are crucial in the development of various inflammatory diseases, including sepsis and autoimmune disorders. The immunosuppressive cytokine INTERLEUKIN (IL)-37 consists of five isoforms (IL-37a-e). We identified IL-37a as a nuclear cytokine for the first time. Compared to IL-37b, IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock. The full-length (FL) form of IL-37a and the N-terminal fragment, which is processed by elastase, could translocate into cell nuclei through a distinctive nuclear localization sequence (NLS)/importin nuclear transport pathway. These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor (PPARγ). This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPβ and H3K4me1/2 to the enhancer/promoter of Pparg. The receptor-independent regulatory pathway of the nuclear IL-37a-PPARγ axis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases, including sepsis.<br /> (© 2023. The Author(s), under exclusive licence to CSI and USTC.)
Details
- Language :
- English
- ISSN :
- 2042-0226
- Volume :
- 20
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Cellular & molecular immunology
- Publication Type :
- Academic Journal
- Accession number :
- 37891333
- Full Text :
- https://doi.org/10.1038/s41423-023-01091-0