title: MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T-cell development upon influenza A virus infection.
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-γ promoter 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.-Köther, K., Nordhoff, C., Masemann, D., Varga, G., Bream, J. H., Gaestel, M., Wixler, V., Ludwig, S. MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T-cell development upon influenza A virus infection.
authors.affiliation: Institute of Molecular Virology (IMV), Centre for Molecular Biology of Inflammation (ZMBE), and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Köther
authors.affiliation: Institute of Molecular Virology (IMV), Centre for Molecular Biology of Inflammation (ZMBE), and.
authors.forename: Carolin
authors.initials: C
authors.lastname: Nordhoff
authors.affiliation: Institute of Molecular Virology (IMV), Centre for Molecular Biology of Inflammation (ZMBE), and.
authors.forename: Dörthe
authors.initials: D
authors.lastname: Masemann
authors.affiliation: Department of Pediatric Rheumatology and Immunology, Westfälische Wilhelms University, Münster, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Varga
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA;
authors.forename: Jay H
authors.initials: JH
authors.lastname: Bream
authors.affiliation: Institute of Biochemistry, Hannover Medical School, Hannover, Germany; and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: Institute of Molecular Virology (IMV), Centre for Molecular Biology of Inflammation (ZMBE), and Interdisciplinary Center of Clinical Research (IZKF), University of Münster, Münster, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Wixler
authors.affiliation: Institute of Molecular Virology (IMV), Centre for Molecular Biology of Inflammation (ZMBE), and Interdisciplinary Center of Clinical Research (IZKF), University of Münster, Münster, Germany ludwigs@uni-muenster.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic; D005786:Gene Expression Regulation; D009980:Influenza A virus; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D007371:Interferon-gamma; C098416:MAP-kinase-activated kinase 3; D017346:Protein Serine-Threonine Kinases
keywords: innate and adaptive immune response; interferon-γ; signal transduction