Bacteroides fragilis enterotoxin induces cyclooxygenase-2 and fluid secretion in intestinal epithelial cells through NF-kappa B activation

Abstract

Bacteroides fragilis produces an approximately 20-kDa heat-labile toxin (B. fragilis enterotoxin, BFT) which is known to be associated with diarrhea. To determine whether cyclooxygenase (COX)-2, via NF-kappa B activation, can contribute to BFT-induced diarrhea, the relationship between COX-2 expression and fluid secretion in BFT-stimulated human intestinal epithelial cells was examined. BFT stimulation increased the expression of COX-2, but not COX-1, in human intestinal epithelial cells. Suppression of the NF-kappa B signal significantly decreased COX-2 expression in response to BFT stimulation. Prostaglandin E-2 (PGE(2)) levels were increased in parallel with COX-2 expression, and, conversely, PGE(2) production was significantly inhibited when COX-2 or NF-kappa B activities were suppressed using COX-2 small interfering RNA (siRNA), p65 NF-kappa B subunit siRNA, or a retrovirus encoding the I kappa B alpha superrepressor. In addition, a selective COX-2 inhibitor, NS-398, significantly inhibited the increased cAMP level induced by BFT stimulation. Furthermore, a selective COX-2 inhibitor prevented BFT-induced PGE(2) production and ileal fluid secretion in a mouse ileal loop model. These results suggest that the secretory response to BFT stimulation may be mediated by the production of PGE(2), through NF-kappa B activation and the up-regulation of COX-2 in intestinal epithelial cells.