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The Journal of Immunology, 2003, 171: 5034-5041.
Copyright © 2003 by The American Association of Immunologists

Reprogramming of IL-10 Activity and Signaling by IFN-{gamma} 1

Carmen Herrero*, Xiaoyu Hu{dagger}, Wai Ping Li*, Stuart Samuels*, M. Nusrat Sharif*, Sergei Kotenko{ddagger} and Lionel B. Ivashkiv2,*,{dagger}

* Department of Medicine, Hospital for Special Surgery, and {dagger} Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021; and {ddagger} Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, Newark, NJ 07103

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.




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