Interleukin‐6 transcriptionally regulates prohibitin expression in intestinal epithelial cells

Abstract

Prohibitin (PHB) is a highly conserved protein and has pleiotropic functions in the cell. We recently demonstrated that PHB expression is decreased during inflammatory bowel disease (IBD) and that PHB protects epithelial cells from oxidant-induced barrier dysfunction. Loss of barrier function is thought to be an inciting event that underlies inflammation in IBD. Therefore, PHB may play an important role in the pathogenesis of intestinal inflammation by acting as a potent antioxidant. Little is known regarding the regulation of PHB expression in intestine or other tissues. The objective of this study was to examine the regulation of PHB expression in intestinal epithelial cells using the model cell line Caco2-BBE. We cloned the 1192 bp human PHB promoter region and identified the transcription start site 1594 bp upstream from the translation start site due to an intervening intron. The acute phase cytokine interleukin-6 (IL-6) increases PHB protein and mRNA abundance and PHB promoter activation. The IL-6 response element in the PHB promoter is required for maximal basal promoter activity and responsiveness to IL-6. IL-6 increases binding of nuclear proteins to the IL-6 response element in the PHB promoter. Basal promoter activity and IL-6 responsiveness are attenuated by SOCS-3 overexpression. Confirming these in vitro results, IL-6−/− mice exhibit reduced PHB expression in the colon compared to WT mice. These results suggest that IL-6 modulates PHB expression in cultured intestinal epithelial cells and in the intestine in vivo, an important insight given that PHB levels are altered in IBD.