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

Pierre C Mccarthy,Victoria A Mcguire,Corinna Greger,Katerina Pardali,Matthias Gaestel,Iain R Phair,Andrew R Clark,J Simon C Arthur

doi:10.1111/imcb.12200

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 intraperitoneal injection of IL‐33.

Highlights

IL-33 is an IL-1-related cytokine that was identified through screening for ligands for the IL-1 receptor family member ST2,1 and it is established as the major in vivo ligand for the ST2 receptor.[2,3,4] Constitutive IL-33 expression has been observed in nonhematopoietic cells, primarily epithelial and endothelial cells
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
IL-33 induced the activation of MSK1, as judged by its phosphorylation on Ser[376], a site that correlates to MSK1 activation,[41] as well as the phosphorylation of the MSK substrate CREB

Summary

INTRODUCTION

IL-33 is an IL-1-related cytokine that was identified through screening for ligands for the IL-1 receptor family member ST2,1 and it is established as the major in vivo ligand for the ST2 receptor.[2,3,4] Constitutive IL-33 expression has been observed in nonhematopoietic cells, primarily epithelial and endothelial cells. A role for p38 in the regulation of cytokine production was initially suggested by the finding that a class of pyridinyl imidazoles typified by SB203580, reduced TNF production via inhibition of p38 This led to the development of a large number of p38 inhibitors, most of which target the p38a and b isoforms, work with gene targeted mice has shown that in macrophages p38a, and not b, is the critical isoform for the regulation of TLR-induced proinflammatory cytokine production.[18] p38a is able to activate further downstream kinases, including MKs and MSKs, which can contribute to the ability of p38 to regulate cytokine production.[18]. We show that the TTP-related protein Brf[1] is expressed in mast cells and is phosphorylated by MK2/3 in these cells following IL-33 stimulation

RESULTS

DISCUSSION

METHODS