title: Critical role of p38 MAPK in IL-4-induced alternative activation of peritoneal macrophages.
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.
authors.affiliation: Unidad de Terapias Farmacológicas. Área de Genética Humana. Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Jiménez-Garcia
authors.forename: Sandra
authors.initials: S
authors.lastname: Herránz
authors.forename: Alfonso
authors.initials: A
authors.lastname: Luque
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Hortelano
mesh_terms: D000818:Animals; D002686:Chitin / Q000494:pharmacology; D005786:Gene Expression Regulation; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000276:immunology*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology
chemical_list: D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D002686:Chitin; D015847:Interleukin-4; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Alternative activation; Chitin; IL-4; JAK/STAT; Macrophages; p38 MAPK