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

• Published in: European journal of immunology 2015-01, Vol.45 (1), p.273-286
• Main Authors: Jiménez‐Garcia, Lidia, Herránz, Sandra, Luque, Alfonso, Hortelano, Sonsoles
• Format: Article
• Language: English
• Subjects: Alternative activation; Animals; Chitin; Chitin - pharmacology; Gene Expression Regulation; IL‐4; Interleukin-4 - genetics; Interleukin-4 - immunology; JAK/STAT; Macrophage Activation - drug effects; Macrophage Activation - immunology; Macrophages; Macrophages, Peritoneal - cytology; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - immunology; Male; Mice; Mice, Inbred C57BL; p38 MAPK; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - immunology; 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; Receptors, Interleukin-4 - genetics; Receptors, Interleukin-4 - immunology; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - immunology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201444806

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.