Reprogramming of IL-10 activity and signaling by IFN-gamma.
One important mechanism of cross-regulation by opposing cytokines is inhibition of signal transduction, including inhibition of Janus kinase-STAT signaling by suppressors of cytokine signaling. We investigated whether IFN-gamma, a major activator of macrophages, inhibited the activity of IL-10, an important deactivator. Preactivation of macrophages with IFN-gamma inhibited two key anti-inflammatory functions of IL-10, the suppression of cytokine production and of MHC class II expression. Gene expression profiling showed that IFN-gamma broadly suppressed the ability of IL-10 to induce or repress gene expression. Although IFN-gamma induced expression of suppressor of cytokine signaling proteins, IL-10 signal transduction was not suppressed and IL-10 activation of Janus kinases and Stat3 was preserved. Instead, IFN-gamma switched the balance of IL-10 STAT activation from Stat3 to Stat1, with concomitant activation of inflammatory gene expression. IL-10 activation of Stat1 required the simultaneous presence of IFN-gamma. These results demonstrate that IFN-gamma operates a switch that rapidly regulates STAT activation by IL-10 and alters macrophage responses to IL-10. Dynamic regulation of the activation of different STATs by the same cytokine provides a mechanism by which cells can integrate and balance signals delivered by opposing cytokines, and extends our understanding of cross-regulation by opposing cytokines to include reprogramming of signaling and alteration of function.
Herrero
Carmen
C
Department of Medicine, Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
Hu
Xiaoyu
X
Li
Wai Ping
WP
Samuels
Stuart
S
Sharif
M Nusrat
MN
Kotenko
Sergei
S
Ivashkiv
Lionel B
LB
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D007371:Interferon-gamma / Q000494:pharmacology* / Q000502:physiology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology
D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma