The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling

Olga Ananieva, Joanne Darragh, Claus Johansen, Julia M. Carr, Joanne McIlrath, Jin Mo Park, Andrew Wingate, Claire E. Monk, Rachel Toth, Susana G. Santos, Lars Iversen, J. Simon C. Arthur (Lead / Corresponding author)

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    Abstract

    The kinases MSK1 and MSK2 are activated 'downstream' of the p38 and Erk1/2 mitogen-activated protein kinases. Here we found that MSK1 and MSK2 were needed to limit the production of proinflammatory cytokines in response to stimulation of primary macrophages with lipopolysaccharide. By inducing transcription of the mitogen-activated protein kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10, MSK1 and MSK2 exerted many negative feedback mechanisms. Deficiency in MSK1 and MSK2 prevented the binding of phosphorylated transcription factors CREB and ATF1 to the promoters of the genes encoding interleukin 10 and DUSP1. Mice doubly deficient in MSK1 and MSK2 were hypersensitive to lipopolysaccharide-induced endotoxic shock and showed prolonged inflammation in a model of toxic contact eczema induced by phorbol 12-myristate 13-acetate. Our results establish MSK1 and MSK2 as key components of negative feedback mechanisms needed to limit Toll-like receptor-driven inflammation.

    Original languageEnglish
    Pages (from-to)1028-1036
    Number of pages9
    JournalNature Immunology
    Volume9
    Issue number9
    DOIs
    Publication statusPublished - Sep 2008

    Cite this

    Ananieva, O., Darragh, J., Johansen, C., Carr, J. M., McIlrath, J., Park, J. M., Wingate, A., Monk, C. E., Toth, R., Santos, S. G., Iversen, L., & Arthur, J. S. C. (2008). The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nature Immunology, 9(9), 1028-1036. https://doi.org/10.1038/ni.1644