Abstract
It has been suggested that prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). We previously observed that the NF-κB activation in colonic epithelial cells is associated with increased tumor necrosis factor receptor 2 (TNFR2) expression in CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC is still unclear. Myosin light chain kinase (MLCK) has been reported to be responsible for the epithelial permeability associated with TNF signaling. Therefore we focused on the role of MLCK expression via TNFR2 signaling on CAC development. Pro-tumorigenic cytokines such as IL-1β, IL-6 and MIP-2 production as well as INF-γ and TNF production at the lamina propria were increased in the setting of colitis, and further in tumor tissues in associations with up-regulated TNFR2 and MLCK expressions in the epithelial cells of a CAC model. The up-regulated MLCK expression was observed in TNF-stimulated colonic epithelial cells in a dose-dependent fashion in association with up-regulation of TNFR2. Silencing TNFR2, but not TNFR1, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. Antibody-mediated blockade of TNF signaling also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results were observed with suppressing TNFR2 and MLCK expressions by inhibiting MLCK in the epithelial cells. Silencing of MLCK also resulted in suppressed TNFR2, but not TNFR1, expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in restored TJ, decreased pro-tumorigenic cytokines and reduced CAC development. These results suggest that MLCK may be a potential target for the prevention of IBD-associated tumor development.
Highlights
The pathogenesis of inflammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis in humans, still remains unclear, chronic epithelial permeability seems to be one of the mechanisms by which extensive inflammatory factors may be introduced into the irritated intestinal tissues
We previously observed that cytokines such as IL-1b, IL-6 and macrophage inflammatory protein (MIP)-2 were up-regulated in an animal model of colitis [6]
Up-regulation of TNFR1 was not remarkable compared to that of tumor necrosis factor receptor 2 (TNFR2). These results indicate that the development of CAC may be associated with the disrupted tight junction (TJ) and elevated pro-tumorigenic cytokines, which are essentially induced by TNFR2 signaling and Myosin light chain kinase (MLCK) expression in the epithelia
Summary
The pathogenesis of inflammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis in humans, still remains unclear, chronic epithelial permeability seems to be one of the mechanisms by which extensive inflammatory factors may be introduced into the irritated intestinal tissues. Previous study had shown that activation of NF-kB in the inflamed tissue is strongly associated with carcinogenesis [5]. In this regard, we have investigated the mechanism of NF-kB activation in the colonic epithelial cells using a murine model of IBD. The specific up-regulation of the type 2 receptor for TNF (TNFR2) was observed in the inflamed intestinal epithelial cells. This observation seems logical since the cytoplasmic domain of TNFR2 can activate NF-kB pathway, but it lacks association with the death domains (DD) like that of TNFR1. The specific role of such NF-kB activation in the inflamed epithelia via TNFR2 signaling in the context of CAC has not been elucidated
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