title: p38α protein negatively regulates T helper type 2 responses by orchestrating multiple T cell receptor-associated signals.
abstract: Mitogen-activated protein kinase p38α is a critical regulator of certain inflammatory diseases. However, its role in T helper type 2 (Th2) responses and allergic inflammation remains unknown. Here we show an increase in the production of interleukin-4 (IL-4) in p38α(-/-) CD4(+) T cells in response to antigen stimulation. p38α-deficient naïve CD4(+) T cells preferentially differentiate into Th2 cells through increased endogenous production of IL-4. Consistent with those results, we also observed decreased expression of p38α during T helper cell differentiation. Furthermore, deficiency of p38α alters the balance in the expression of NFATc1 and NFATc2 under steady-state conditions and enhances the expression and nuclear translocation of NFATc1 in CD4(+) T cells upon antigen stimulation. Knockdown of NFATc1 significantly inhibits Th2 differentiation in p38α(-/-) T cells but not in p38α(+/-) T cells. p38α deficiency also inhibits the activation of Akt but enhances the activation of ERK in response to T cell receptor engagement without impacting IL-2/Stat5 signaling. In a model of ovalbumin-induced acute allergic airway inflammation, mice with induced deletion of p38α show elevated serum ovalbumin-specific IgE level, increased infiltration of eosinophils, and higher concentrations of Th2 cytokines including IL-4 and IL-5 in the bronchoalveolar lavage fluid relative to control mice. Taken together, p38α regulates multiple T cell receptor-associated signals and negatively influences Th2 differentiation and allergic inflammation.
authors.affiliation: Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.forename: Angel R
authors.initials: AR
authors.lastname: Nebreda
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
authors.forename: Mark
authors.initials: M
authors.lastname: Kaplan
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D007107:Immune System; D007249:Inflammation; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D018418:Th2 Cells / Q000201:enzymology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D050778:NFATC Transcription Factors; D015847:Interleukin-4; D048308:Mitogen-Activated Protein Kinase 14