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-γ 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-γ 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-γ and immune complexes.
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2 June 2003
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June 02 2003
Inhibition of Interleukin 10 Signaling after Fc Receptor Ligation and during Rheumatoid Arthritis
Jong-Dae Ji,
Jong-Dae Ji
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
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Ioannis Tassiulas,
Ioannis Tassiulas
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
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Kyung-Hyun Park-Min,
Kyung-Hyun Park-Min
2Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University
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Ani Aydin,
Ani Aydin
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
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Ingrid Mecklenbräuker,
Ingrid Mecklenbräuker
3Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY 10021
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Alexander Tarakhovsky,
Alexander Tarakhovsky
3Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY 10021
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Luminita Pricop,
Luminita Pricop
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
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Jane E. Salmon,
Jane E. Salmon
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
2Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University
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Lionel B. Ivashkiv
Lionel B. Ivashkiv
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
2Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University
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Jong-Dae Ji
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
Ioannis Tassiulas
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
Kyung-Hyun Park-Min
2Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University
Ani Aydin
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
Ingrid Mecklenbräuker
3Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY 10021
Alexander Tarakhovsky
3Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY 10021
Luminita Pricop
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
Jane E. Salmon
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
2Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University
Lionel B. Ivashkiv
1Department of Medicine Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University
2Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University
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: [email protected]
*
Abbreviations used in this paper: DAG, diacyl glycerol; EMSA, electrophoretic mobility shift assay; IC, immune complex; PKC, protein kinase C; RA, rheumatoid arthritis; SOCS, suppressors of cytokine signaling; STAT, signal transducer and activator of transcription.
Received:
October 16 2002
Revision Received:
April 08 2003
Accepted:
April 21 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 197 (11): 1573–1583.
Article history
Received:
October 16 2002
Revision Received:
April 08 2003
Accepted:
April 21 2003
Citation
Jong-Dae Ji, Ioannis Tassiulas, Kyung-Hyun Park-Min, Ani Aydin, Ingrid Mecklenbräuker, Alexander Tarakhovsky, Luminita Pricop, Jane E. Salmon, Lionel B. Ivashkiv; Inhibition of Interleukin 10 Signaling after Fc Receptor Ligation and during Rheumatoid Arthritis . J Exp Med 2 June 2003; 197 (11): 1573–1583. doi: https://doi.org/10.1084/jem.20021820
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