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J. Biol. Chem., Vol. 282, Issue 10, 6965-6975, March 9, 2007

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Expression of Constitutively Active STAT3 Can Replicate the Cytokine-suppressive Activity of Interleukin-10 in Human Primary Macrophages^*

From the Kennedy Institute of Rheumatology Division, Imperial College London, ARC Building, 1 Aspenlea Road, London W6 8LH, United Kingdom

There is general agreement that signal transducer and activation of transcription 3 (STAT3) is required to mediate the anti-inflammatory activities of interleukin (IL)-10. However, STAT3 is activated by multiple factors that do not share the anti-inflammatory activity of IL-10. The question remains whether STAT3 is sufficient for the anti-inflammatory effects or whether there are other signals required, as had been suggested previously. We set out to map the human IL-10 receptor and to identify the key elements involved in transducing the cytokine-suppressive effects of IL-10. We were able to show an absolute requirement for both of the tyrosine residues found within the YXXQ-STAT3-docking site within the IL-10 receptor 1 and that no other signals appeared to be required. We used a constitutively active STAT3 to determine whether expression of this factor could suppress lipopolysaccharide-induced tumor necrosis factor and IL-6 production. Our data show that STAT3 activity can suppress both IL-6 and tumor necrosis factor production in lipopolysaccharide-stimulated macrophages. However, in synovial fibroblasts, STAT3 did not suppress IL-6 production, suggesting that the cellular environment plays an important role in dictating whether STAT3 drives a pro- or anti-inflammatory response.

Received for publication, September 26, 2006 , and in revised form, December 1, 2006.

^* This work was supported by the Biotechnology and Biological Sciences Research Council, Wellcome Trust and the British Heart Foundation. 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 To whom correspondence should be addressed. Tel.: 44-208-383-4429; Fax: 44-208-383-4499; E-mail: b.foxwell{at}imperial.ac.uk.

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