Mechanisms of transcriptional modulation of the human anion exchanger SLC26A3 gene expression by IFN-γ

Saksena S, Singla A, Goyal S, Katyal S, Bansal N, Gill RK, Alrefai WA, Ramaswamy K, Dudeja PK. Mechanisms of transcriptional modulation of the human anion exchanger SLC26A3 gene expression by IFN-gamma. Am J Physiol Gastrointest Liver Physiol 298: G159-G166, 2010. First published November 25, 2009; doi:10.1152/ajpgi.00374.2009.-Two members of the SLC26 gene family, SLC26A3 or DRA (downregulated in adenoma) and SLC26A6 (putative anion transporter 1, PAT1), are known to play a major role in apical Cl-/OH- (HCO3-) exchange process in the human intestine. We have previously shown the inhibitory effects of IFN-gamma (30 ng/ml, 24 h) on both SLC26A3 and A6 expression and promoter activity. We also demonstrated that the effects of IFN-gamma on SLC26A6 gene expression were mediated via IRF- 1 transcription factor. However, the molecular mechanisms underlying the transcriptional modulation of SLC26A3 gene expression by IFN-gamma in the intestine are not known. The present studies were, therefore, designed to elucidate the signaling mechanisms and transcription factor(s) involved in mediating the inhibitory effects of IFN-gamma on DRA promoter (p- -1183/+114) activity. Deletion analysis indicated that the IFN-gamma response element is located within the -1183 to -790 region, and sequence analysis of this region revealed the presence of potential gamma-activated site (GAS), a binding site (-933/-925 bp) for signal transducer and activator of transcription factor 1 (STAT1). Mutations in the potential GAS element abrogated the inhibitory effects of IFN-gamma. These studies provide evidence for the involvement of STAT1 in the inhibition of SLC26A3 gene expression by IFN-gamma in the human intestine.