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Inhibition of Interleukin 10 Signaling after Fc Receptor Ligation and during Rheumatoid Arthritis

Jong-Dae Ji¹, Ioannis Tassiulas¹, Kyung-Hyun Park-Min², Ani Aydin¹, Ingrid Mecklenbräuker³, Alexander Tarakhovsky³, Luminita Pricop¹, Jane E. Salmon^1,2 and Lionel B. Ivashkiv^1,2

¹ Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
² Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University
³ Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY 10021

Address correspondence to Lionel B. Ivashkiv, Hospital for Special Surgery, 535 East 70th St., New York, NY 10021. Phone: 212-606-1653; Fax: 212-774-2337; E-mail: ivashkivl{at}hss.edu

Interleukin-10 (IL-10) is a potent deactivator of myeloid cells that limits the intensity and duration of immune and inflammatory responses. The activity of IL-10 can be suppressed during inflammation, infection, or after allogeneic tissue transplantation. We investigated whether inflammatory factors suppress IL-10 activity at the level of signal transduction. Out of many factors tested, only ligation of Fc receptors by immune complexes inhibited IL-10 activation of the Jak-Stat signaling pathway. IL-10 signaling was suppressed in rheumatoid arthritis joint macrophages that are exposed to immune complexes in vivo. Activation of macrophages with interferon- was required for Fc receptor–mediated suppression of IL-10 signaling, which resulted in diminished activation of IL-10–inducible genes and reversal of IL-10–dependent suppression of cytokine production. The mechanism of inhibition involved decreased cell surface IL-10 receptor expression and Jak1 activation and was dependent on protein kinase C delta. These results establish that IL-10 signaling is regulated during inflammation and identify Fc receptors and interferon- as important regulators of IL-10 activity. Generation of macrophages refractory to IL-10 can contribute to pathogenesis of inflammatory and infectious diseases characterized by production of interferon- and immune complexes.

Key Words: interleukin 10 • Fc receptor • signal transduction • Jak-Stat • macrophage

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