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 language | English (US) |
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Pages (from-to) | 4235-4246 |
Number of pages | 12 |
Journal | FASEB Journal |
Volume | 28 |
Issue number | 10 |
DOIs | |
State | Published - Oct 1 2014 |
Keywords
- Innate and adaptive immune response
- Interferon-γ
- Signal transduction
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics