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J. Biol. Chem., Vol. 281, Issue 20, 14111-14118, May 19, 2006

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Role of STAT3 in Type I Interferon Responses

NEGATIVE REGULATION OF STAT1-DEPENDENT INFLAMMATORY GENE ACTIVATION^*

Hao H. Ho and Lionel B. Ivashkiv¹

From the Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery and the Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10021

Type I interferons (IFN/) induce antiviral responses and have immunomodulatory effects that can either promote or suppress immunity and inflammation. In myeloid cells IFN/ activates signal transducers and activators of transcription STAT1, STAT2, and STAT3. STAT1 and STAT2 mediate the antiviral and inflammatory effects of IFN/, but the function of IFN/-activated STAT3 is not known. We investigated the role of STAT3 in type I IFN signaling in myeloid cells by modulating STAT3 expression and the intensity of STAT3 activation using overexpression and RNA interference and determining the effects on downstream signaling and gene expression. IFN-activated STAT3 inhibited STAT1-dependent gene activation, thereby down-regulating IFN-mediated induction of inflammatory mediators such as the chemokines CXCL9 (Mig) and CXCL10 (IP-10). At the same time, IFN-activated STAT3 supported ISGF-3-dependent induction of antiviral genes. STAT3 did not suppress STAT1 tyrosine phosphorylation or nuclear translocation but instead sequestered STAT1 and suppressed the formation of DNA-binding STAT1 homodimers. These results identify a regulatory function for STAT3 in attenuating the inflammatory properties of type I IFNs and provide a mechanism of suppression of STAT1 function that differs from previously described suppression of tyrosine phosphorylation. The results suggest that changes in the relative expression and activation of STAT1 and STAT3 that occur during immune responses determine the nature of cellular responses to type I IFNs.

Received for publication, November 1, 2005 , and in revised form, March 13, 2006.

^* This work was supported by grants from the National Institutes of Health. 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: Dept. of Medicine, Hospital for Special Surgery, 535 East 70th St., New York, NY 10021. Tel.: 212-606-1653; Fax: 212-774-2337; E-mail: ivashkivl{at}hss.edu.

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