Inhibition of JAKs in macrophages increases lipopolysaccharide-induced cytokine production by blocking IL-10-mediated feedback

Michael J. Pattison, Kirsty F. MacKenzie, J. Simon C. Arthur (Lead / Corresponding author)

    Research output: Contribution to journalArticle

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    Abstract

    Macrophages are an important source of cytokines following infection. Stimulation of macrophages with TLR agonists results in the secretion of TNF-a, IL-6, and IL-12, and the production of these cytokines is controlled by multiple feedback pathways. Macrophages also produce IL-10, which acts to inhibit proinflammatory cytokine production by macrophages via a JAK/STAT3-dependent pathway. We show in this paper that, Ruxolitinib, a recently described selective inhibitor of JAKs, increases TNF, IL-6, and IL-12 secretion in mouse bone marrow-derived macrophages stimulated with LPS. This effect is largely due to its ability to block IL-10-mediated feedback inhibition on cytokine transcription in macrophages. Similar results were also obtained with a second structurally unrelated Jak inhibitor, Tofacitinib. In addition, LPS induced the production of IFN-ß, which was then able to activate JAKs in macrophages, resulting in the stimulation of STAT1 phosphorylation. The initial induction of IL-10 was independent of JAK signaling; however, inhibition of JAKs did reduce IL-10 secretion at later time points. This reflected a requirement for the IFN-ß feedback loop to sustain IL-10 transcription following LPS stimulation. In addition to IL-10, IFN-ß also helped sustain IL-6 and IL-12 transcription. Overall, these results suggest that inhibition of JAKs may increase the inflammatory potential of macrophages stimulated with TLR4 agonists.
    Original languageEnglish
    Pages (from-to)2784-2792
    Number of pages9
    JournalJournal of Immunology
    Volume189
    Issue number6
    DOIs
    Publication statusPublished - 2012

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    Interleukin-10
    Lipopolysaccharides
    Macrophages
    Cytokines
    Interleukin-12
    Interleukin-6
    Phosphorylation
    Infection

    Cite this

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    title = "Inhibition of JAKs in macrophages increases lipopolysaccharide-induced cytokine production by blocking IL-10-mediated feedback",
    abstract = "Macrophages are an important source of cytokines following infection. Stimulation of macrophages with TLR agonists results in the secretion of TNF-a, IL-6, and IL-12, and the production of these cytokines is controlled by multiple feedback pathways. Macrophages also produce IL-10, which acts to inhibit proinflammatory cytokine production by macrophages via a JAK/STAT3-dependent pathway. We show in this paper that, Ruxolitinib, a recently described selective inhibitor of JAKs, increases TNF, IL-6, and IL-12 secretion in mouse bone marrow-derived macrophages stimulated with LPS. This effect is largely due to its ability to block IL-10-mediated feedback inhibition on cytokine transcription in macrophages. Similar results were also obtained with a second structurally unrelated Jak inhibitor, Tofacitinib. In addition, LPS induced the production of IFN-{\ss}, which was then able to activate JAKs in macrophages, resulting in the stimulation of STAT1 phosphorylation. The initial induction of IL-10 was independent of JAK signaling; however, inhibition of JAKs did reduce IL-10 secretion at later time points. This reflected a requirement for the IFN-{\ss} feedback loop to sustain IL-10 transcription following LPS stimulation. In addition to IL-10, IFN-{\ss} also helped sustain IL-6 and IL-12 transcription. Overall, these results suggest that inhibition of JAKs may increase the inflammatory potential of macrophages stimulated with TLR4 agonists.",
    author = "Pattison, {Michael J.} and MacKenzie, {Kirsty F.} and Arthur, {J. Simon C.}",
    note = "Copyright 2012 Elsevier B.V., All rights reserved.",
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    Inhibition of JAKs in macrophages increases lipopolysaccharide-induced cytokine production by blocking IL-10-mediated feedback. / Pattison, Michael J.; MacKenzie, Kirsty F.; Arthur, J. Simon C. (Lead / Corresponding author).

    In: Journal of Immunology, Vol. 189, No. 6, 2012, p. 2784-2792.

    Research output: Contribution to journalArticle

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    AU - Pattison, Michael J.

    AU - MacKenzie, Kirsty F.

    AU - Arthur, J. Simon C.

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