The Kinase p38 Alpha Serves Cell Type-Specific Inflammatory Functions in Skin Injury and Coordinates Pro- And Anti-Inflammatory Gene Expression

Nat Immunol. 2008 Sep;9(9):1019-27. doi: 10.1038/ni.1640.

Abstract

The mitogen-activated protein kinase p38 mediates cellular responses to injurious stress and immune signaling. Among the many p38 isoforms, p38 alpha is the most widely expressed in adult tissues and can be targeted by various pharmacological inhibitors. Here we investigated how p38 alpha activation is linked to cell type-specific outputs in mouse models of cutaneous inflammation. We found that both myeloid and epithelial p38 elicit inflammatory responses, yet p38 alpha signaling in each cell type served distinct inflammatory functions and varied depending on the mode of skin irritation. In addition, myeloid p38 alpha limited acute inflammation via activation of anti-inflammatory gene expression dependent on mitogen- and stress-activated kinases. Our results suggest a dual function for p38 alpha in the regulation of inflammation and show mixed potential for its inhibition as a therapeutic strategy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured / metabolism
  • Disease Models, Animal
  • Epithelial Cells
  • Gene Expression / drug effects
  • Inflammation / immunology*
  • Inflammation Mediators / metabolism*
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Myeloid Cells
  • Protein Kinase Inhibitors / pharmacology
  • Skin Diseases / genetics
  • Skin Diseases / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / physiology*

Substances

  • Inflammation Mediators
  • Protein Kinase Inhibitors
  • p38 Mitogen-Activated Protein Kinases