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Kotlyarov, A, Neininger, A, Schubert, C, Eckert, R, Birchmeier, C, Volk, HD and Gaestel, M (1999) MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat. Cell Biol. 1:94-7
MAPKAP kinase 2 (MK2) is one of several kinases that are regulated through direct phosphorylation by p38 MAP kinase. By introducing a targeted mutation into the mouse MK2 gene, we have determined the physiological function of MK2 in vivo. Mice that lack MK2 show increased stress resistance and survive LPS-induced endotoxic shock. This is due to a reduction of approximately 90% in the production of tumor necrosis factor-alpha (TNF-alpha) and not to a change in signalling from the TNF receptor. The level and stability of TNF-alpha mRNA is not reduced and TNF-alpha secretion is not affected. We conclude that MK2 is an essential component in the inflammatory response which regulates biosynthesis of TNF-alpha at a post-transcriptional level.
Animals; Cytokines/biosynthesis; Cytokines/genetics; Gene Expression Regulation/drug effects; Gene Expression Regulation/physiology; Inflammation/genetics; Inflammation/immunology; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides/pharmacology; Mice; Mice, Inbred Strains; Mice, Knockout; Mitogen-Activated Protein Kinases/metabolism; Mutagenesis; Phosphorylation; Protein-Serine-Threonine Kinases/deficiency; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; RNA, Messenger/metabolism; Restriction Mapping; Salmonella typhi; Spleen/immunology; Transcription, Genetic; Tumor Necrosis Factor-alpha/biosynthesis; Tumor Necrosis Factor-alpha/genetics; p38 Mitogen-Activated Protein Kinases