Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation

Chiara Berlato, Marco A. Cassatella, Ichiko Kinjyo, Luana Gatto, Akihiko Yoshimura, Flavia Bazzoni

Research output: Contribution to journalArticle

207 Citations (Scopus)

Abstract

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-α, 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-α, 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-α 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.

Original languageEnglish
Pages (from-to)6404-6411
Number of pages8
JournalJournal of Immunology
Volume168
Issue number12
Publication statusPublished - 2002 Jun 15
Externally publishedYes

Fingerprint

Macrophage Activation
Interleukin-10
Lipopolysaccharides
Cytokines
Messenger RNA
Interleukin-6
Macrophages
Genes
Peritoneal Macrophages
Granulocyte-Macrophage Colony-Stimulating Factor
Nitric Oxide Synthase
Transfection
Tyrosine
Monocytes
Neutrophils
Phosphorylation
Cell Line

ASJC Scopus subject areas

  • Immunology

Cite this

Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. / Berlato, Chiara; Cassatella, Marco A.; Kinjyo, Ichiko; Gatto, Luana; Yoshimura, Akihiko; Bazzoni, Flavia.

In: Journal of Immunology, Vol. 168, No. 12, 15.06.2002, p. 6404-6411.

Research output: Contribution to journalArticle

Berlato, Chiara ; Cassatella, Marco A. ; Kinjyo, Ichiko ; Gatto, Luana ; Yoshimura, Akihiko ; Bazzoni, Flavia. / Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. In: Journal of Immunology. 2002 ; Vol. 168, No. 12. pp. 6404-6411.
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