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.