During active intestinal inflammation as in inflammatory bowel disease, large numbers of neutrophils and monocytes migrate into the inflamed mucosa and submucosa carrying out a series of destructive effector events leading to tissue destruction. This suggests the presence of potent chemotactic molecules, such as IL-8 and MCP-1, both of which are more resistant to inactivation by peptidases and proteases than C5a and LTB4. Evidence has accumulated demonstrating that intestinal epithelial cells may participate in the mucosal immune responses by secreting IL-8 and MCP-1 in addition to their primary role of nutrient absorption and barrier defense. The mechanism linking the luminal environment containing nutrients, bacteria, and its products (short chain fatty acids), to intestinal epithelial cell function is not fully understood. Butyrate, a short chain fatty acid, is the principal energy yielding substrate for colonocytes. We have shown that butyrate induces a chemokine switch between IL-8 and MCP-1 in enterocytes. The overall hypothesis is that butyrate causes an alteration of the chromatin structure of chromosomes 4 (IL-8) and chromosome 17 (MCP-1) leading to divergent transcriptional regulation of IL-8 and MCP-1 synthesis in enterocytes. The long term goal is to determine the molecular regulatory mechanisms of the effects of butyrate in altering enterocyte gene expression of chemokines, IL-8 and MCP-1. To achieve this goal, the specific aims proposed are 1) to examine the role of butyrate on the initiation of transcription of IL-8 and MCP-1; 2) to investigate the effect of butyrate on the interaction between the promoters of IL-8 and MCP-1 and nuclear binding proteins; 3) to examine the effect of butyrate on the interaction between chromatin and IL-8 and MCP-1 genes; 4) to study the molecular regulation of the effects of butyrate on IL-8 and MCP-1 production in freshly isolated intestinal epithelial cells obtained from organ cultures of human fetal small intestine; and 5).to elucidate the molecular regulation of the in vivo effects of butyrate on the secretion of IL-8 and MCP-1 by human intestinal epithelial cell obtained from human fetal intestinal tissues transplanted into athymic nude mice as a xenograft. The knowledge gained from this experiments will increase our understanding of how manipulations in diet might influence intestinal mucosal immune responses.
| Fusunyan, R D; Nanthakumar, N N; Baldeon, M E et al. (2001) Evidence for an innate immune response in the immature human intestine: toll-like receptors on fetal enterocytes. Pediatr Res 49:589-93 |
