Interferon-γ expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway

Mercedes Rincon, Hervé Enslen, Joël Raingeaud, Michael Recht, Tyler Zapton, Michael S S Su, Laurie A. Penix, Roger J. Davis, Richard A. Fiavell

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349 Scopus citations

Abstract

Signal transduction via MAP kinase pathways plays a key role in a variety of cellular responses, including growth factor-induced proliferation, differentiation and cell death. In mammalian cells, p38 MAP kinase can be activated by multiple stimuli, such as pro-inflammatory cytokines and environmental stress. Although p38 MAP kinase is implicated in the control of inflammatory responses, the molecular mechanisms remain unclear. Upon activation, CD4+ T cells differentiate into Th2 cells, which potentiate the humoral immune response or pro-inflammatory Th1 cells. Here, we show that pyridinyl imidazole compounds (specific inhibitors of p38 MAP kinase) block the production of interferon-γ (IFNγ) by Th1 cells without affecting IL-4 production by Th2 cells. These drugs also inhibit transcription driven by the IFNγ promoter. In transgenic mice, inhibition of the p38 MAP kinase pathway by the expression of dominant-negative p38 MAP kinase results in selective impairment of Th1 responses, In contrast, activation of the p38 MAP kinase pathway by the expression of constitutively-activated MAP kinase kinase 6 in transgenic mice caused increased production of IFNγ during the differentiation and activation of Th1 cells. Together, these data demonstrate that the p38 MAP kinase is relevant for Th1 cells, not Th2 cells, and that inhibition of p38 MAP kinase represents a possible site of therapeutic intervention in diseases where a predominant Th1 immune response leads to a pathological outcome. Moreover, our study provides an additional mechanism by which the p38 MAP kinase pathway controls inflammatory responses.

Original languageEnglish (US)
Pages (from-to)2817-2829
Number of pages13
JournalEMBO Journal
Volume17
Issue number10
DOIs
Publication statusPublished - May 15 1998
Externally publishedYes

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Keywords

  • IFNγ
  • p38 MAP kinase
  • T-cell differentiation
  • Th1 cells
  • Transgenic mice

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Rincon, M., Enslen, H., Raingeaud, J., Recht, M., Zapton, T., Su, M. S. S., ... Fiavell, R. A. (1998). Interferon-γ expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway. EMBO Journal, 17(10), 2817-2829. https://doi.org/10.1093/emboj/17.10.2817