Inhibition of JAKs in Macrophages Increases Lipopolysaccharide-Induced Cytokine Production by Blocking IL-10–Mediated Feedback

  • Pattison M
  • MacKenzie K
  • Arthur J
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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-α, 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-β, 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-β feedback loop to sustain IL-10 transcription following LPS stimulation. In addition to IL-10, IFN-β 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.

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Pattison, M. J., MacKenzie, K. F., & Arthur, J. S. C. (2012). Inhibition of JAKs in Macrophages Increases Lipopolysaccharide-Induced Cytokine Production by Blocking IL-10–Mediated Feedback. The Journal of Immunology, 189(6), 2784–2792. https://doi.org/10.4049/jimmunol.1200310

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