IL-33 regulates cytokine production and neutrophil recruitment via the p38 MAPK-activated kinases MK2/3.

Immunology and Cell Biology
Pierre C McCarthyJ Simon C Arthur

Abstract

IL-33 is an IL-1-related cytokine that can act as an alarmin when released from necrotic cells. Once released, it can target various immune cells including mast cells, innate lymphoid cells and T cells to elicit a Th2-like immune response. We show here that bone marrow-derived mast cells produce IL-13, IL-6, TNF, GM-CSF, CCL3 and CCL4 in response to IL-33 stimulation. Inhibition of the p38 MAPK, or inhibition or knockout of its downstream kinases MK2 and MK3, blocked the production of these cytokines in response to IL-33. The mechanism downstream of MK2/3 was cytokine specific; however, MK2 and MK3 were able to regulate TNF and GM-CSF mRNA stability. Previous studies in macrophages have shown that MK2 regulates mRNA stability via phosphorylation of the RNA-binding protein TTP (Zfp36). The regulation of cytokine production in mast cells was, however, independent of TTP. MK2/3 were able to phosphorylate the TTP-related protein Brf1 (Zfp36 l1) in IL-33-stimulated mast cells, suggesting a mechanism by which MK2/3 might control mRNA stability in these cells. In line with its ability to regulate in vitro IL-33-stimulated cytokine production, double knockout of MK2 and 3 in mice prevented neutrophil recruitment following intraperitone...Continue Reading

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Citations

Feb 28, 2020·Scientific Reports·Tsvetana PetrovaJ Simon C Arthur
Jun 21, 2020·International Journal of Molecular Sciences·Pio ContiGianpaolo Ronconi
Jul 23, 2020·Frontiers in Immunology·Caroline ChauchéHenry J McSorley
Jan 29, 2021·Nature Reviews. Molecular Cell Biology·Begoña Canovas, Angel R Nebreda
Feb 19, 2021·The Journal of Biological Chemistry·Nicola J DarlingPhilip Cohen
Aug 7, 2021·Journal of Multidisciplinary Healthcare·Meirong Xu, Ganlin Wu

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Methods Mentioned

BETA
flow cytometry
pulldowns
FCS
Protein Assay
pulldown
FACS

Software Mentioned

Excel
iScript
SigmaPlot

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