P38α protein negatively regulates T helper type 2 responses by orchestrating multiple T cell receptor-associated signals

Ping Hu, Angel R. Nebreda, Yan Liu, Nadia Carlesso, Mark Kaplan, Reuben Kapur

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)33215-33226
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number40
DOIs
StatePublished - Sep 28 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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