Differential expression of TGF-beta isoforms by normal and inflammatory bowel disease intestinal myofibroblasts

First publishedSeptember 5, 2001; 10.1152/ajpcell. 00048.2001.Intestinalstrictures are frequent in Crohn's disease but not ulcerative colitis.We investigated the expression of transforming growth factor (TGF)-isoforms by isolated and cultured primary human intestinalmyofibroblasts and the responsiveness of these cells and intestinalepithelial cells to TGF- isoforms. Normal intestinal myofibroblastsreleased predominantly TGF-₃ and ulcerative colitismyofibroblasts expressed both TGF-₁ andTGF-₃, whereas in myofibroblast cultures from fibroticCrohn's disease tissue, there was significantly lower expression ofTGF-₃ but enhanced release of TGF-₂.These distinctive patterns of TGF- isoform release were sustainedthrough several myofibroblast passages. Proliferation of Crohn'sdisease myofibroblasts was significantly greater than that ofmyofibroblasts derived from normal and ulcerative colitis tissue. Incontrast to cells from normal and ulcerative colitis tissue,neutralization of the three TGF- isoforms did not affect theproliferation of Crohn's disease intestinal myofibroblasts. Studies onthe effect of recombinant TGF- isoforms on epithelial restitutionand proliferation suggest that TGF-₂ may be the least effective of the three isoforms in intestinal wound repair. In conclusion, the enhanced release of TGF-₂ but reducedexpression of TGF-₃ by Crohn's disease intestinalmyofibroblasts, together with their enhanced proliferative capacity,may lead to the development of intestinal strictures.

     

Human colonic subepithelial myofibroblasts modulate transepithelial resistance and secretory response

The epithelium of the gastrointestinal tracttransports ions and water but excludes luminal microorganisms and toxicmolecules. The factors regulating these important functions are notfully understood. Intestinal myofibroblasts lie subjacent to thebasement membrane, at the basal surface of epithelial cells. Werecently showed that primary cultures of adult human colonicsubepithelial myofibroblasts express cyclooxygenase (COX)-1 and COX-2enzymes and release bioactive transforming growth factor- (TGF-).In this study we have investigated the role of normal human colonic subepithelial myofibroblasts in the regulation of transepithelial resistance and secretory response in HCA-7 and T84 colonic epithelial cell lines. Cocultures of epithelial cells-myofibroblasts and mediumconditioned by myofibroblasts enhanced transepithelial resistance anddelayed mannitol flux. A panspecific antibody to TGF- (but notpiroxicam) antagonized this effect. In HCA-7 cells, myofibroblastsdownregulated secretagogue-induced change in short-circuit current, andthis effect was reversed by pretreatment of myofibroblasts withpiroxicam. In contrast to HCA-7 cells, myofibroblasts upregulated theagonist-induced secretory response in T84 cells. This study shows thatintestinal subepithelial myofibroblasts enhance barrier function andmodulate electrogenic chloride secretion in epithelial cells. Theenhancement of barrier function was mediated by TGF-. In contrast,the modulation of agonist-induced change in short-circuit current wasmediated by cyclooxygenase products. These findings suggest thatcolonic myofibroblasts regulate important functions of epithelial cellsvia distinct secretory products.