MSK1 and MSK2 inhibit lipopolysaccharide-induced prostaglandin production via an interleukin-10 feedback loop

Kirsty F. MacKenzie, Mirjam W. M. Van den Bosch, Shaista Naqvi, Suzanne E. Elcombe, Victoria A. McGuire, Alastair D. Reith, Perry J. Blackshear, Jonathan L. E. Dean, J. Simon C. Arthur

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    33 Citations (Scopus)

    Abstract

    Prostaglandin production is catalyzed by cyclooxygenase 2 (cox-2). We demonstrate here that MSK1 and MSK2 (MSK1/2) can exert control on the induction of cox-2 mRNA by Toll-like receptor (TLR) agonists. In the initial phase of cox-2 induction, MSK1/2 knockout macrophages confirmed a role for MSK in the positive regulation of transcription. However, at later time points both lipopolysaccharide (LPS)-induced prostaglandin and cox-2 protein levels were increased in MSK1/2 knockout. Further analysis found that while MSKs promoted cox-2 mRNA transcription, following longer LPS stimulation MSKs also promoted degradation of cox-2 mRNA. This was found to be the result of an interleukin 10 (IL-10) feedback mechanism, with endogenously produced IL-10 promoting cox-2 degradation. The ability of IL-10 to do this was dependent on the mRNA binding protein TTP through a p38/MK2-mediated mechanism. As MSKs regulate IL-10 production in response to LPS, MSK1/2 knockout results in reduced IL-10 secretion and therefore reduced feedback from IL-10 on cox-2 mRNA stability. Following LPS stimulation, this increased mRNA stability correlated to an elevated induction of both of cox-2 protein and prostaglandin secretion in MSK1/2 knockout macrophages relative to that in wild-type cells. This was not restricted to isolated macrophages, as a similar effect of MSK1/2 knockout was seen on plasma prostaglandin E-2 (PGE(2)) levels following intraperitoneal injection of LPS.

    Original languageEnglish
    Pages (from-to)1456-1467
    Number of pages12
    JournalMolecular and Cellular Biology
    Volume33
    Issue number7
    DOIs
    Publication statusPublished - Apr 2013

    Keywords

    • NF-KAPPA-B
    • STRESS-INDUCED PHOSPHORYLATION
    • NECROSIS-FACTOR-ALPHA
    • ACTIVATED PROTEIN-KINASE
    • CYCLOOXYGENASE-2 MESSENGER-RNA
    • P38 MAPK PATHWAY
    • 3'-UNTRANSLATED REGION
    • RAW 264.7 MACROPHAGES
    • BINDING-PROTEIN
    • GENE-TRANSCRIPTION

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  • Cite this

    MacKenzie, K. F., Van den Bosch, M. W. M., Naqvi, S., Elcombe, S. E., McGuire, V. A., Reith, A. D., Blackshear, P. J., Dean, J. L. E., & Arthur, J. S. C. (2013). MSK1 and MSK2 inhibit lipopolysaccharide-induced prostaglandin production via an interleukin-10 feedback loop. Molecular and Cellular Biology, 33(7), 1456-1467. https://doi.org/10.1128/MCB.01690-12