Inhibition of interferon gamma signaling by the short chain fatty acid butyrate.
The short chain fatty acid butyrate promotes proliferation and survival of normal epithelial cells, but induces G(1) or G(2)-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-gamma is one of the principle cytokines secreted by lamina propria cells in inflamed mucosa and elevated levels of the transcription factor required for IFN-gamma 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-gamma. We demonstrated that this short chain fatty acid inhibits IFN-gamma-induced tyrosine and serine phosphorylation of STAT1. IFN-gamma-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 (gamma-activated sites) revealed that butyrate inhibits IFN-gamma induced, STAT1-dependent, transcriptional activation. Proinflammatory cytokines, including IFN-gamma, 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-gamma/STAT1 signaling.
D002087:Butyrates / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D053614:Janus Kinase 2; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D002087:Butyrates; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D010768:Phosphoserine; D019000:Phosphotyrosine; D007371:Interferon-gamma; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2