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Cutting Edge: A Transcriptional Repressor and Corepressor Induced by the STAT3-Regulated Anti-Inflammatory Signaling Pathway¹

Karim C. El Kasmi^2,*, Amber M. Smith^*, Lynn Williams, Geoffrey Neale, Athanasia Panopolous, Stephanie S. Watowich, Hans Häcker^*, Brian M. J. Foxwell and Peter J. Murray^3,*

^* Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105; Kennedy Institute of Rheumatology, Imperial College London, Hammersmith, London, United Kingdom; Hartwell Center for Biotechnology and Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN 38105; and Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030

IL-10 regulates anti-inflammatory signaling via the activation of STAT3, which in turn controls the induction of a gene expression program whose products execute inhibitory effects on proinflammatory mediator production. In this study we show that IL-10 induces the expression of an ETS family transcriptional repressor, ETV3, and a helicase family corepressor, Strawberry notch homologue 2 (SBNO2), in mouse and human macrophages. IL-10-mediated induction of ETV3 and SBNO2 expression was dependent upon both STAT3 and a stimulus through the TLR pathway. We also observed that ETV3 expression was strongly induced by the STAT3 pathway regulated by IL-10 but not by STAT3 signaling activated by IL-6, which cannot activate the anti-inflammatory signaling pathway. ETV3 and SBNO2 repressed NF-B- but not IFN regulatory factor 7 (IRF7)-activated transcriptional reporters. Collectively our data suggest that ETV3 and SBNO2 are components of the pathways that contribute to the downstream anti-inflammatory effects of IL-10.

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 This work was supported by grants to P.J.M. from the National Institutes of Health, the Sandler Program for Asthma Research, and the American Lebanese Syrian Associated Charities and by Cancer Center CORE Grant P30 CA 21765; by grants to A.P. from National Institutes of Health (T32-CA-09598-16) and the American Legion (American Legion Auxiliary Award); and by grants to S.S.W. from the American Heart Association Texas Affiliate (0455143Y), the Gillson Longenbaugh Foundation, and the MD Anderson Cancer Center Institutional Grants Program.

² Current address: University of Colorado Health Sciences Center, Denver, CO 80218.

³ Address correspondence and reprint requests to Dr. Peter J. Murray, Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105. E-mail address: peter.murray{at}stjude

⁴ Abbreviations used in this paper: AIR, anti-inflammatory response; BMDM, bone marrow-derived macrophage; IRF7, IFN regulatory factor 7; qRT-PCR, quantitative RT-PCR; siRNA, small interfering RNA; SBNO2, Strawberry notch homologue 2; SOCS3, suppressor of cytokine signaling 3.