Degeneration of the Pericryptal Myofibroblast Sheath by Proinflammatory Cytokines in Inflammatory Bowel Diseases

Background & Aims: Inflammatory bowel diseases (IBDs) are characterized by remodeling of the intestinal mucosa, which is associated with excessive cytokine release. Previous studies have shown that the epithelium in the crypt region of the mucosa in patients with Crohn's disease is susceptible to proinflammatory cytokines. We investigated whether the subepithelial myofibroblasts in this region were affected by these inflammatory conditions. Methods: Immunofluorescence and immunohistochemistry were performed on inflamed and uninflamed specimens from patients with IBD to detect alpha-smooth muscle actin (alpha SMA), desmin, and tenascin-C. The effects of the proinflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma were analyzed in human intestinal myofibroblast cultures by immunoblotting and apoptosis assays. Results: Immunofluorescence analysis revealed decreased levels of the extracellular matrix molecule tenascin-C in pericryptal sheaths and alpha SMA in the immediate vicinity of the crypts in the inflamed specimens, indicating that the myofibroblast pericryptal sheath is affected by proinflammatory cytokines. Although individual cytokines did not affect myofibroblast proliferation or survival, cytokine combinations triggered caspase-dependent apoptosis. alpha SMA levels were reduced significantly in cells exposed to cytokines, either alone or in combination, suggesting dedifferentiation of myofibroblasts. Proinflammatory cytokines did not affect tenascin-C expression, suggesting that the decrease observed in the inflamed mucosa resulted from myofibroblast apoptosis. Conclusions: The subepithelial myofibroblasts of the epithelial sheath are disrupted in the intestinal mucosa of patients with IBD. A loss of myofibroblasts appears to result from the susceptibility of these cells to proinflammatory cytokines.