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Signaling and Regulation

Inhibition of Interferon Signaling by the Short Chain Fatty Acid Butyrate¹

¹ Albert Einstein Cancer Center, Montefiore Medical Center, Department of Oncology, Bronx, NY, and
² Research Institute, International Medical Center of Japan, Toyama 1-21-1, Shinjuku-ku, Tokyo, Japan

Requests for reprints: Lidija Klampfer, Albert Einstein Cancer Center, Montefiore Medical Center, 111 E. 210th Street, Bronx NY 10467. Phone: (718) 920-6579; Fax: (718) 882-4464. E-mail: lklampf{at}aecom.yu.edu

The short chain fatty acid butyrate promotes proliferation and survival of normal epithelial cells, but induces G₁ or G₂-M arrest in transformed cells, which is coupled to differentiation and apoptosis. Local administration of butyrate has been shown to ameliorate inflammation in ulcerative colitis; however, the precise mechanism of its anti-inflammatory activity is not known. IFN- is one of the principle cytokines secreted by lamina propria cells in inflamed mucosa and elevated levels of the transcription factor required for IFN- signaling, STAT1 (signal transducer and activator of transcription 1), are present in the colonic mucosa of patients with ulcerative colitis and Crohn's disease. Here we report that butyrate is a strong inhibitor of signaling by IFN-. We demonstrated that this short chain fatty acid inhibits IFN--induced tyrosine and serine phosphorylation of STAT1. IFN--induced JAK2 activation was inhibited by butyrate, implicating JAK2 as a target of butyrate action. Accordingly, STAT1 nuclear translocation and its DNA binding were completely inhibited in butyrate-treated cells. Transient transfection experiments using a reporter gene construct containing eight GAS sites (-activated sites) revealed that butyrate inhibits IFN- induced, STAT1-dependent, transcriptional activation. Proinflammatory cytokines, including IFN-, play an important role in the pathogenesis of inflammatory bowel disease, and abnormal activity of STAT1 is associated with human malignancies and intestinal inflammatory diseases. Thus, our data suggest that butyrate negatively regulates mucosal inflammation through the inhibition of IFN-/STAT1 signaling.

Key Words: Inflammation • STAT1 • chemoprevention • ulcerative colitis • colon cancer

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