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MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis

Abstract

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 90 % in the production of tumor necrosis factor-α (TNF-α) and not to a change in signalling from the TNF receptor. The level and stability of TNF-α mRNA is not reduced and TNF-α secretion is not affected. We conclude that MK2 is an essential component in the inflammatory response which regulates biosynthesis of TNF-α at a post-transcriptional level.

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Figure 1: Strategy applied to mutate the MK2 gene and effect of the mutation on MK2 activity and Hsp25 phosphorylation.
Figure 2: Effect of LPS/d-gal on the survival and the production of TNF-α and NO in MK2 mutant mice.
Figure 3: Germinal centre formation in spleens of wild-type (+/+) and MK2-deficient (–/–) mice after immunization with TNP-keyhole limpet haemocyanin (TNP-KLH).
Figure 4: Analysis of cytokine mRNA levels and TNF-α secretion in spleen cells.

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Acknowledgements

We thank U.E. Höpken for plasmids and E. Fietze (Humboldt-University, Berlin) and R. Förster (MDC, Berlin) for histomorphological analysis of tissue samples. We thank G. Schwedersky, U. Gerhardt and K. Laaß for technical assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft and the European Community.

Correspondence should be addressed to M.G.

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Correspondence to Matthias Gaestel.

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Kotlyarov, A., Neininger, A., Schubert, C. et al. MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis . Nat Cell Biol 1, 94–97 (1999). https://doi.org/10.1038/10061

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