Regulation of Zfp36 by ISGF3 and MK2 restricts the expression of inflammatory cytokines during necroptosis stimulation.

Autor: Yadav S; Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada., El Hamra R; Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada., Alturki NA; Clinical Laboratory Science Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia., Ariana A; Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada., Bhan A; Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada., Hurley K; Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada., Gaestel M; Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany., Blackshear PJ; Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, United States of America., Blais A; Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.; Ottawa Institute of Systems Biology, Ottawa, ON, Canada.; University of Ottawa, Centre for Infection Immunity and Inflammation, Ottawa, ON, Canada.; University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada., Sad S; Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. subash.sad@uottawa.ca.; University of Ottawa, Centre for Infection Immunity and Inflammation, Ottawa, ON, Canada. subash.sad@uottawa.ca.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Aug 08; Vol. 15 (8), pp. 574. Date of Electronic Publication: 2024 Aug 08.
DOI: 10.1038/s41419-024-06964-4
Abstrakt: Necrosome activation following TLR- or cytokine receptor-signaling results in cell death by necroptosis which is characterized by the rupture of cell membranes and the consequent release of intracellular contents to the extracellular milieu. While necroptosis exacerbates various inflammatory diseases, the mechanisms through which the inflammatory responses are regulated are not clear. We show that the necrosome activation of macrophages results in an upregulation of various pathways, including the mitogen-activated protein kinase (MAPK) cascade, which results in an elevation of the inflammatory response and consequent expression of several cytokines and chemokines. Programming for this upregulation of inflammatory response occurs during the early phase of necrosome activation and proceeds independently of cell death but depends on the activation of the receptor-interacting protein kinase-1 (RipK1). Interestingly, necrosome activation also results in an upregulation of IFNβ, which in turn exerts an inhibitory effect on the maintenance of inflammatory response through the repression of MAPK-signaling and an upregulation of Zfp36. Activation of the interferon-induced gene factor-3 (ISGF3) results in the expression of ZFP36 (TTP), which induces the post-transcriptional degradation of mRNAs of various inflammatory cytokines and chemokines through the recognition of AU-rich elements in their 3'UTR. Furthermore, ZFP-36 inhibits IFNβ-, but not TNFα- induced necroptosis. Overall, these results reveal the molecular mechanism through which IFNβ, a pro-inflammatory cytokine, induces the expression of ZFP-36, which in turn inhibits necroptosis and halts the maintenance of the inflammatory response.
(© 2024. The Author(s).)
Databáze: MEDLINE
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