MK2/3 Are Pivotal for IL-33-Induced and Mast Cell-Dependent Leukocyte Recruitment and the Resulting Skin Inflammation

J Immunol. 2016 Nov 1;197(9):3662-3668. doi: 10.4049/jimmunol.1600658. Epub 2016 Sep 30.

Abstract

The IL-1R family member IL-33R mediates Fcε-receptor-I (FcεRI)-independent activation of mast cells leading to NF-κB activation and consequently the production of cytokines. IL-33 also induces the activation of MAPKs, such as p38. We aimed to define the relevance of the p38-targets, the MAPK-activated protein kinases 2 and 3 (MK2 and MK3) in IL-33-induced signaling and the resulting mast cell effector functions in vitro and in vivo. We demonstrate that the IL-33-induced IL-6 and IL-13 production strongly depends on the MK2/3-mediated activation of ERK1/2 and PI3K signaling. Furthermore, in the presence of the stem cell factors, IL-33 did induce an MK2/3-, ERK1/2- and PI3K-dependent production of TNF-α. In vivo, the loss of MK2/3 in mast cells decreased the IL-33-induced leukocyte recruitment and the resulting skin inflammation. Therefore, the MK2/3-dependent signaling in mast cells is essential to mediate IL-33-induced inflammatory responses. Thus, MK2/3 are potential therapeutic targets for suppression of IL-33-induced inflammation skin diseases such as psoriasis.

MeSH terms

  • Animals
  • Cell Movement
  • Cells, Cultured
  • Inflammation / immunology*
  • Inflammation Mediators / metabolism
  • Interleukin-33 / immunology*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Leukocytes / immunology*
  • MAP Kinase Signaling System
  • Mast Cells / immunology*
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Psoriasis / immunology*
  • Skin / immunology*

Substances

  • Inflammation Mediators
  • Interleukin-33
  • Intracellular Signaling Peptides and Proteins
  • MAP-kinase-activated kinase 2
  • MAP-kinase-activated kinase 3
  • Protein Serine-Threonine Kinases