Modulation of Intestinal Epithelial Physiology and Signal Transduction by Transforming Growth Factor-beta

Abstract

<p>Intestinal epithelia contribute to gut homeostasis by acting as a selectively permeable barrier and establishing a driving force for water movement through vectorial ion transport. These processes are affected by cytokines. As TGFß levels can be increased in gut inflammation, a situation where epithelial function is often altered. the aim of this thesis was to d.efine the effeets of TGFß on intestinal epithelial barrier and ion transport function. The first study characterized the kinetics and signal transduction pathway behind the novel observation that intestinal epithelial monolayers treated with TGFß display reduced stimulated secretory responses. The mechanisms involved in this process were further delineated in a second study where it was determined TGFp treatment causes a down-regulation and altered sub-cellular localization of the main apical chloride channel (CFTR). The final study defined the mechanism behind TGFp-induced epithelial barrier enhancement in terms of signal transduction pathways and regulation of proteins involved in maintaining a physiologically "tight" barrier. Furthermore, it was determined that TGFß treatment protects against barrier damage caused by pathogenic bacteria, and the mechanisms behind this have been revealed. The first two manuscripts present a substantial body of evidence on the kinetics and mechanisms of TGFß-induced diminished epithelial ion transport. In addition to furthering understanding of cytokine regulation of epithelial function, these data are particularly relevant to the field of enteric disease where water balance is often perturbed. In the tinal manuscript, the protective role of TGFß on epithelial barrier function is illustrated by its ability to preserve banier function from damage caused by the pathogenic bacteria. enterohemonhagic E. coli (EHEC) 0157:H7. Having determined mechanisms underlying ephhelial banier enhancement and protection by TGF~, potential therapeutic targets have been revealed that might be strategic in treating individuals with conditions of increased banier permeability. such as inflammatory bowel disease relapses and EHEC infection.</p>