MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T-cell development upon influenza A virus infection

Katharina Köther, Carolin Nordhoff, Dörthe Masemann, Georg Varga, Jay H. Bream, Matthias Gaestel, Viktor Wixler, Stephan Ludwig

Research output: Contribution to journalArticle

Abstract

MK2 and MK3 are downstream targets of p38 and ERK1/2. They control the mRNA stability of several inflammatory cytokines, including TNF-α and IL-10. Whereas MK2 is expressed ubiquitously, the expression of MK3 is restricted to muscle, liver, and heart tissues and T and NK cells. Using Mk-deficient and wild-type (WT) mice, we demonstrated an inhibitory effect of MK3, but not of MK2, on interferon (IFN)-γ expression in T and NK lymphocytes. The results provided evidence that the inhibitory effect of MK3 is based on negative feedback phosphorylation of p38 and ERK1/2, which causes decreased binding of Stat4 to the IFN-γpromoter and reduced expression of IFN-γ mRNA and protein. Consequently, all Mk3-/- mice challenged with the Th1-inducing influenza A virus (IAV) survived the WT LD50 virus dose. The reduced disease severity in the Mk3-/- mice was accompanied by a >10-fold reduction in viral lung titer and an increase in the number of activated NK cells and enhanced Th1 activation of CD4 T cells. Thus, our data describe the protein kinase MK3 as a novel regulator of the innate and adaptive immune responses.

Original languageEnglish (US)
Pages (from-to)4235-4246
Number of pages12
JournalFASEB Journal
Volume28
Issue number10
DOIs
StatePublished - Oct 1 2014

Keywords

  • Innate and adaptive immune response
  • Interferon-γ
  • Signal transduction

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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