| Abstract |
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 diseases
characterized by production of interferon-γ and immune complexes.
A key role of IFNs in innate immunity is the priming of cells for enhanced
cellular responses to cytokines and microbial antigens. The molecular basis of priming is
not completely understood. Here we investigated the effects of priming macrophages
with low concentrations of IFN-γ on subsequent responses to type I IFNs (IFN-α/β). IFN-
γ preferentially enhanced STAT1 activation by type I IFNs, with concomitant increased
activation of inflammatory STAT1 target genes, and increased IFN-α-dependent
recruitment of cells in a murine model of lupus. Enhanced IFN-α STAT1 activation in
IFN-γ-primed macrophages did not require STAT2 or Tyk2, but was dependent on Syk,
and on the FcR gamma adapter protein that activates Syk via immunoreceptor tyrosine
activation motifs. Forced expression of Syk in non-hematopoietic cells resulted in
enhanced IFN-α activation of STAT1. Syk associated with STAT1 in a ligand-dependent
manner, and could phosphorylate and thereby activate STAT1. Enhanced STAT1
activation by type I IFNs was amplified by increased STAT1 expression that occurs
during IFN-γ priming. These results identify a two component mechanism of
amplification of Jak-STAT signaling that is mediated by Syk and STAT1 and is specific
for hematopoietic cells that express Syk.
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Ο ρόλος των κυτταροκινών (IL-10 και IFN-α) στην παθογένεια χρόνιων φλεγμονωδών αυτοάνοσων παθήσεων
