Inhibition of apoptosis in Bacteroides fragilis enterotoxin-stimulated intestinal epithelial cells through the induction of c-IAP-2

Eur J Immunol. 2008 Aug;38(8):2190-9. doi: 10.1002/eji.200838191.


Enterotoxigenic Bacteroides fragilis produces an approximately 20-kDa heat-labile enterotoxin (BFT) that plays an essential role in generating mucosal inflammation. Although it is well known that proinflammatory signals are expressed in BFT-stimulated intestinal epithelial cells, cell death processes have not been elucidated. BFT induced apoptosis in HT-29 cells, but the apoptosis was first apparent 36 h after stimulation. During the early period of BFT stimulation, expression of cellular inhibitor of apoptosis protein-2 (c-IAP2) increased, and inhibition of c-IAP2 augmented the apoptotic cell death. Inhibition of BFT-induced COX-2 expression decreased prostaglandin E(2) (PGE(2)) production, which led not only to a decrease of c-IAP2 activity but also to an enhancement of DNA fragmentation in the early period of BFT stimulation. Furthermore, apoptosis inhibition through PGE(2) and c-IAP2 was mainly regulated by a p38 mitogen-activated protein kinase (MAPK). These results suggest that the inhibition of apoptosis may be mediated by a sequential pathway, including MAPK, COX-2, PGE(2) and c-IAP2, in the early period of stimulation. The delay in the onset of epithelial cell apoptosis after enterotoxigenic B. fragilis infection may be important to the host since it can provides sufficient time for epithelial cells to generate signals for the activation of mucosal inflammation and it may increase the chances of bacterial colonization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Bacteroides fragilis / pathogenicity*
  • Cyclooxygenase 2 / physiology
  • Dinoprostone / physiology
  • Enterotoxins / toxicity*
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • HT29 Cells
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / physiology*
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / pathology
  • RNA, Messenger / analysis
  • p38 Mitogen-Activated Protein Kinases / physiology


  • Enterotoxins
  • Inhibitor of Apoptosis Proteins
  • RNA, Messenger
  • Cyclooxygenase 2
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Dinoprostone