Inhibition of interleukin 10 signaling after Fc receptor ligation and during rheumatoid arthritis

• Published in: The Journal of experimental medicine Vol. 197; no. 11; pp. 1573 - 1583
• Main Authors: Ji, Jong-Dae, Tassiulas, Ioannis, Park-Min, Kyung-Hyun, Aydin, Ani, Mecklenbrauker, Ingrid, Tarakhovsky, Alexander, Pricop, Luminita, Salmon, Jane E, Ivashkiv, Lionel B
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 02.06.2003
• Subjects: Antigen-Antibody Complex - metabolism; Arthritis, Rheumatoid - immunology; Base Sequence; DNA - genetics; Humans; In Vitro Techniques; Interferon-gamma - metabolism; Interleukin-10 - metabolism; Macrophage Activation; Macrophages - immunology; Macrophages - metabolism; Protein Kinase C - metabolism; Receptors, IgG - metabolism; Signal Transduction
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20021820

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-gamma 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-gamma 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-gamma and immune complexes.