Journal
FASEB JOURNAL
Volume 28, Issue 10, Pages 4235-4246Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-249599
Keywords
interferon-gamma; signal transduction; innate and adaptive immune response
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Funding
- Interdisciplinary Center of Clinical Research (IZKF) at the University of Munster [Lud2/010/11, Lud2/017/13]
- Graduate School [GRK1409]
- Collaborative Research Center [SFB1009]
- Deutsche Forschungsgemeinschaft (DFG)
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MK2 and MK3 are downstream targets of p38 and ERK1/2. They control the mRNA stability of several inflammatory cytokines, including TNF-alpha 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)-gamma 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-gamma promoter and reduced expression of IFN-gamma 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.
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