Bacteroides fragilis enterotoxin induces cyclooxygenase-2 and fluid secretion in intestinal epithelial cells through NF-kappaB activation.
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-kappaB 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-kappaB signal significantly decreased COX-2 expression in response to BFT stimulation. Prostaglandin E2 (PGE2) levels were increased in parallel with COX-2 expression, and, conversely, PGE2 production was significantly inhibited when COX-2 or NF-kappaB activities were suppressed using COX-2 small interfering RNA (siRNA), p65 NF-kappaB subunit siRNA, or a retrovirus encoding the IkappaBalpha 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 PGE2 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 PGE2, through NF-kappaB activation and the up-regulation of COX-2 in intestinal epithelial cells.
Kim
Jung Mogg
JM
Department of Microbiology and Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, Korea. jungmogg@hanyang.ac.kr
Lee
Jin Young
JY
Yoon
Young Mee
YM
Oh
Yu-Kyoung
YK
Kang
Ju Seop
JS
Kim
Yeong-Jeon
YJ
Kim
Kyoung-Ho
KH
D000818:Animals; D001441:Bacteroides fragilis / Q000276:immunology*; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000187:drug effects; D003967:Diarrhea / Q000209:etiology; D015232:Dinoprostone / Q000096:biosynthesis; D004768:Enterotoxins / Q000009:adverse effects / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D004768:Enterotoxins; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D034741:RNA, Small Interfering; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D015232:Dinoprostone