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

Nature Immunology volume 9, pages 1028–1036 (2008)Cite this article

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.

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Figure 1: MSK is activated by TLR signaling.
Figure 2: Deficiency in MSK1 and MSK2 results in more production of proinflammatory cytokines in response to LPS.
Figure 3: MSKs regulate Dusp1 transcription in macrophages.
Figure 4: MSK regulates LPS-induced IL-10 production.
Figure 5: MSK-induced IL-10 production inhibits IL-6 and IL-12 production.
Figure 6: Il10 and Dusp1 promoters associate with phosphorylated CREB and/or ATF1.
Figure 7: Involvement of MSK1 and MSK2 in the sensitivity of mice to inflammation in vivo.
Figure 8: Involvement of MSK1 and MSK2 in the sensitivity of mice to PMA-induced eczema.

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Acknowledgements

We thank A. O'Garra (National Institute of Medical Research, London) for the IL-10-neutralizing antibody. Supported by the UK Medical Research Council, Arthritis Research Campaign, Novo Nordic Foundation, Danish Research Agency, Astra-Zeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, and Pfizer.

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Authors and Affiliations

  1. Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK

    Olga Ananieva, Joanne Darragh, Julia M Carr, Joanne McIlrath, Andrew Wingate, Claire E Monk, Rachel Toth, Susana G Santos & J Simon C Arthur

  2. Department of Dermatology, Aarhus University Hospital, Aarhus C, DK-8000, Denmark

    Claus Johansen & Lars Iversen

  3. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Jin Mo Park

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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 and J Simon C Arthur

Supported in part by the Division of Signal Transduction Therapy (Dundee), which is funded by Astra-Zeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Pfizer.

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Ananieva, O., Darragh, J., Johansen, C. et al. The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nat Immunol 9, 1028–1036 (2008). https://doi.org/10.1038/ni.1644

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