Critical role of p38 MAPK in IL-4-induced alternative activation of peritoneal macrophages

Eur J Immunol. 2015 Jan;45(1):273-86. doi: 10.1002/eji.201444806. Epub 2014 Nov 24.

Abstract

Alternative activation of macrophages plays an important role in a range of physiological and pathological processes. This alternative phenotype, also known as M2 macrophages, is induced by type 2 cytokines such as IL-4. The binding of IL-4 to its receptor leads to activation of two major signaling pathways: STAT-6 and PI3K. However, recent studies have described that p38 MAPK might play a role in IL-4-dependent signaling in some cells, although its role in macrophages is still controversial. In this study, we investigated whether p38 MAPK plays a role in the polarization of macrophages in mice. Our results reveal that IL-4 induces phosphorylation of p38 MAPK in thioglycollate-elicited murine peritoneal macrophages, in addition to STAT-6 and PI3K activation. Furthermore, p38 MAPK inactivation, by gene silencing or pharmacological inhibition, suppressed IL-4-induced typical M2 markers, indicating the involvement of p38 MAPK in the signaling of IL-4 leading to M2-macrophage polarization. Moreover, p38 MAPK inhibition blocked phosphorylation of STAT-6 and Akt, suggesting that p38 MAPK is upstream of these signaling pathways. Finally, we show that in an in vivo model of chitin-induced M2 polarization, p38 MAPK inhibition also diminished activation of M2 markers. Taken together, our data establish a new role for p38 MAPK during IL-4-induced alternative activation of macrophages.

Keywords: Alternative activation; Chitin; IL-4; JAK/STAT; Macrophages; p38 MAPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chitin / pharmacology
  • Gene Expression Regulation
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology*
  • Macrophage Activation / drug effects
  • Macrophage Activation / immunology*
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / immunology
  • Phosphorylation
  • Primary Cell Culture
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / immunology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Interleukin-4 / genetics
  • Receptors, Interleukin-4 / immunology*
  • STAT6 Transcription Factor / genetics
  • STAT6 Transcription Factor / immunology
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics*
  • p38 Mitogen-Activated Protein Kinases / immunology

Substances

  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Receptors, Interleukin-4
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Chitin
  • Interleukin-4
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases