Inhibition of interleukin 10 signaling after Fc receptor ligation and during rheumatoid arthritis.
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.[1]References
- Inhibition of interleukin 10 signaling after Fc receptor ligation and during rheumatoid arthritis. Ji, J.D., Tassiulas, I., Park-Min, K.H., Aydin, A., Mecklenbrauker, I., Tarakhovsky, A., Pricop, L., Salmon, J.E., Ivashkiv, L.B. J. Exp. Med. (2003) [Pubmed]
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