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J. Biol. Chem., Vol. 281, Issue 10, 6316-6324, March 10, 2006

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Divergent Mechanisms Utilized by SOCS3 to Mediate Interleukin-10 Inhibition of Tumor Necrosis Factor and Nitric Oxide Production by Macrophages^*

Pooran Qasimi¹, Andrew Ming-Lum, Ali Ghanipour¹, Christopher J. Ong^¶, Michael E. Cox^¶, James Ihle^||, Nicolas Cacalano^**, Akihiko Yoshimura, and Alice L-F. Mui²

From the Department of Surgery, University of British Columbia, Immunity and Infection Research Centre and ^¶Prostate Cancer Reseach Centre, Vancouver Coastal Health Research Institute, Vancouver, British Columbia V6H 3Z6 Canada, the ^||St. Jude Children's Research Hospital, Memphis, Tennessee 38105, the ^**Department of Radiation Oncology, University of California, Los Angeles, California 90095, and the Division of Molecular and Cellular Immunology, Kyushu University, Fukuoka 812-8582, Japan

The cytokine interleukin-10 (IL-10) potently inhibits macrophage function through activation of the transcription factor STAT3. The expression of SOCS3 (suppressor of cytokine signaling-3) has been shown to be induced by IL-10 in a STAT3-dependent manner. However, the relevance of SOCS3 expression to the anti-inflammatory effect of IL-10 on macrophages has been controversial. Through kinetic analysis of the requirement for SOCS3 in IL-10 inhibition of lipopolysaccharide (LPS)-stimulated tumor necrosis factor- (TNF) transcription and translation, SOCS3 was found to be necessary for TNF expression during the early phase, but not the late phase of IL-10 action. SOCS3 was essential for IL-10 inhibition of LPS-stimulated production of iNOS (inducible nitric-oxide synthase) protein and nitric oxide (NO). To determine the domains of SOCS3 protein important in mediating these effects, SOCS3^–/– macrophages were reconstituted with SOCS3 mutated for the SH2, KIR, SOCS box domains, and tyrosines 204 (Tyr²⁰⁴) and 221 (Tyr²²¹). The SH2 domain, SOCS box, and both Tyr²⁰⁴ and Tyr²²¹ were required for IL-10 inhibition of TNF mRNA and protein expression, but interestingly the KIR domain was necessary only for IL-10 inhibition of TNF protein expression. In contrast, Tyr²⁰⁴ and Tyr²²¹ were the only structural features of SOCS3 that were necessary in mediating IL-10 inhibition of iNOS protein expression and NO production. These data define SOCS3 as an important mediator of IL-10 inhibition of macrophage activation and that SOCS3 interferes with distinct LPS-stimulated signal transduction events through differing mechanisms.

Received for publication, August 4, 2005 , and in revised form, November 29, 2005.

^* This work was supported in part by a grant from the Canadian Institutes of Health Research (to A. L.-F. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by studentships from the Canadian Institutes of Health Research/Michael Smith Health Research Foundation Training Program in Transplantation.

² To whom correspondence should be addressed: Jack Bell Research Centre, 2660 Oak St., Vancouver, British Columbia V6H 3Z6, Canada. E-mail: amui{at}interchange.ubc.ca.

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