Research ArticleInflammation

The early synthesis of p35 and activation of CDK5 in LPS-stimulated macrophages suppresses interleukin-10 production

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Sci. Signal.  24 Nov 2015:
Vol. 8, Issue 404, pp. ra121
DOI: 10.1126/scisignal.aab3156

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Taking the time to inflame

In response to the microbial product lipopolysaccharide (LPS), macrophages produce inflammatory cytokines to fight infection; however, they also produce anti-inflammatory cytokines, such as interleukin-10 (IL-10), to resolve the inflammation. Na et al. highlighted the temporal regulation of these responses by finding that LPS also stimulated the early and transient synthesis of p35, a protein that binds to and activates cyclin-dependent kinase 5 (CDK5). The CDK5-p35 complex prevented macrophages from producing IL-10 and other anti-inflammatory factors. Mice deficient in p35 showed enhanced IL-10 production and were protected from tissue damage in a model of chemical-induced gut inflammation. Together, these data suggest that the early activation of CDK5 delays the production of IL-10 and the onset of anti-inflammatory processes.

Abstract

Interleukin-10 (IL-10) is an important anti-inflammatory cytokine that is produced primarily by macrophages. We investigated mechanisms by which the timing of IL-10 production was controlled in macrophages and found that cyclin-dependent kinase 5 (CDK5) activity was markedly increased in lipopolysaccharide (LPS)–stimulated macrophages through the synthesis of the CDK5-binding partner and activator p35. Degradation of p35 released the inhibition on anti-inflammatory signaling mediated by CDK5-p35 complexes. The transiently active CDK5-p35 complexes limited the LPS-stimulated phosphorylation and activation of various mitogen-activated protein kinases (MAPKs), thereby preventing the premature production of SOCS3 (suppressor of cytokine signaling 3), an inhibitor of inflammatory responses in macrophages, and IL-10. Furthermore, we showed that dextran sodium sulfate failed to induce colitis in p35-deficient mice, which was associated with the enhanced production of IL-10 by macrophages. Together, our results suggest that CDK5 enhances the inflammatory function of macrophages by inhibiting the MAPK-dependent production of IL-10.

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