Enhanced Expression of Transcription Factor GATA-4 in Inflammatory Bowel Disease and Its Possible Regulation by TGF-β1

Abstract

Transforming growth factor beta 1 (TGF-beta1) promotes epithelial healing in inflammatory bowel disease. We hypothesized that GATA-4, a transcription factor cooperating with TGF-beta signaling pathway, is upregulated by TGF-beta1 in the inflamed intestinal epithelium. Normal and inflamed intestinal samples were subjected to immunohistochemistry for GATA-4/6 and the TGF-beta signaling pathway components Smad2/3/4. Proliferation and apoptosis were analyzed using Ki-67 and in situ DNA 3'-end labeling assays and Bax and Bcl-2 immunohistochemistry. Furthermore, GATA-4 was assessed in intestinal Caco-2 cells stimulated with TGF-beta1, or interleukin-6 and tumor necrosis factor alpha. GATA-4 was detected in only 20% of normal intestinal samples, but was upregulated in corresponding inflamed regions. GATA-6 expression remained unchanged during inflammation. TGF-beta1 and Smad3/4, but not Smad2, were expressed concomitantly with GATA-4 in inflamed bowel mucosa. In intestinal Caco-2 cells, TGF-beta1 upregulated GATA-4 and Smad2/3/4, whereas treatment with control cytokines had no effect. Inflammation was associated with increased epithelial cell apoptosis and the enhancement of Bcl-2, but not Bax. We surmise GATA-4 expression is upregulated in inflamed intestine correlating with the activation of TGF-beta signaling pathway. We speculate that TGF-beta1 drives GATA-4 expression during intestinal inflammation, these two components cooperating to promote epithelial healing.