The studies outlined in this proposal will focus on the role of transforming growth factor-beta (TGF-beta) in the mechanisms which govern the immune functions of intestinal epithelial cells as related to an inflammatory response at the intestinal mucosa. As a model system, we will use the nontransformed rat intestinal epithelial cell line, IEC-6. We have previously found that TGF-beta could enhance secretory component (SC) and class I major histocompatibility antigen (MHC) expression on IEC-6 cells. TGF-beta was also found to enhance the secretion of the inflammatory cytokine interleukin-6 (IL-6) by IEC-6 cells, as were IL-1alpha, IL-1beta, and TNF-alpha (all inflammatory cytokines themselves) able to induce IL-6 secretion by these cells. Co-stimulation of the IEC-6 cells with TGF-beta and either IL-1 or TNF-alpha resulted in a synergistic enhancement of IL-6 secretion by the IEC-6 cells to levels much greater than that of both cytokines combined. Preliminary results indicate that TGF-beta induced the IEC-6 cells to become more sensitive to IL-1 stimulation, an effect which was partially due to an enhanced expression of IL-1 receptors induced by TGF-beta. However, high levels of both TGF-beta and IL-1beta tended to lower the synergistic effect on IL-6 responses by the IEC-8 cells. In this proposal, we will (10 investigate the effect of TGF-beta on the expression of mRNA for SC as well as the effect of other cytokines in combination with TGF-beta. (2) The regulation of IL-6 secretion by TGF-beta with or without other inflammatory cytokines will be determined using a cytokine specific bioassay, RNA and protein synthesis inhibitors, and mRNA analysis to monitor the induction of and secretion of IL-6. (3) The effect of TGF-beta on the expression of receptors for the inflammatory cytokines will be explored in order to yield insight as to a possible mechanism whereby TGF- beta could enhance the effectiveness of these cytokines to induce IL-6 secretion. (4) The mechanism by which high levels of TGF-beta limit the synergistic effect of TGF-beta and IL-1beta on IL-6 secretion will be studied to determine if IL-6 mRNA or protein synthesis and IL-1 receptor expression are altered by high levels of these cytokines. (5) The effect of TGF-beta on the secretion of other inflammatory cytokines such as IL-1 and TNF-alpha will be assessed by specific assays and mRNA analysis. Finally, (6) the effect of TGF-beta on IL-6 secretion (and possibly the secretion of other cytokines) by IEC-6 cells induced with bacterial lipopolysaccharide will be studied as a model of the response of IEC to bacterial agents. The proposed study should lend valuable insight as to the role of TGF-beta and the intestinal epithelial cell in mucosal inflammatory responses such as those seen with mucosal infections and inflammatory bowel disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First Independent Research Support & Transition (FIRST) Awards (R29)
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General Medicine A Subcommittee 2 (GMA)
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University of Alabama Birmingham
Schools of Dentistry
United States
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