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* Department of Pathology, Section of General Pathology, University of Verona, Verona, Italy; and
Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Previous studies have shown that IL-10 can induce the expression of
the suppressor of cytokine signaling 3 (SOCS-3) mRNA in human monocytes
and neutrophils, suggesting that the capacity of IL-10 to inhibit the
expression of LPS-inducible proinflammatory genes may depend on SOCS-3
induction. However, no direct experimental evidence has been provided
to support such hypothesis. Herein, we show that stable transfection of
SOCS-3 into the mouse macrophage cell line J774 resulted in an
inhibition of NO, TNF-
, IL-6, and GM-CSF secretion in response to
LPS at levels similar to those exerted by IL-10 in LPS-stimulated
wild-type J774. Constitutive SOCS-3 expression also down-regulated the
mRNA expression of inducible NO synthase and IL-6 and impaired the
production of TNF-, mainly at a post-transcriptional level. In
addition, SOCS-3-transfected cells displayed a constitutive expression
of the IL-1R antagonist gene, consistent with the observation that
IL-10 enhances IL-1R antagonist mRNA in LPS-stimulated wild-type cells.
Furthermore, in peritoneal macrophages harvested from mice carrying
heterozygous disruption of the SOCS-3 gene, IL-10 was less effective in
repressing LPS-stimulated TNF- and NO production. Taken together,
our data show that SOCS-3 inhibits LPS-induced macrophage activation,
strongly supporting the idea that it plays a role in the molecular
mechanism by which IL-10 down-modulates the effector functions of
LPS-activated macrophages. Finally, we show that forced expression of
SOCS-3 significantly suppresses the ability of IL-10 to trigger
tyrosine phosphorylation of STAT3. Therefore, SOCS-3 functions both as
an LPS signal inhibitor and as a negative feedback regulator of
IL-10/STAT3 signaling.
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