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

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 intraperitoneal injection of IL‐33.