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.
Ji
Jong-Dae
JD
Department of Medicine Hospital for Special Surgery, 535 East 70th St., New York, NY 10021, USA.
Tassiulas
Ioannis
I
Park-Min
Kyung-Hyun
KH
Aydin
Ani
A
Mecklenbrauker
Ingrid
I
Tarakhovsky
Alexander
A
Pricop
Luminita
L
Salmon
Jane E
JE
Ivashkiv
Lionel B
LB
D000936:Antigen-Antibody Complex / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction
D000936:Antigen-Antibody Complex; D017452:Receptors, IgG; D016753:Interleukin-10; D007371:Interferon-gamma; D004247:DNA; D011493:Protein Kinase C