Inhibition of apoptosis inBacteroides fragilisenterotoxin-stimulated intestinal epithelial cells through the induction of c-IAP-2

Enterotoxigenic Bacteroides fragilis (ETBF) secretes a 20-kDa metalloprotease toxin termed B. fragilis toxin (BFT). ETBF disease in animals is associated with an acute inflammatory response in the intestinal mucosa, and lethal hemorrhagic colitis may occur in rabbits. In this study, we confirmed recent reports (J. M. Kim, Y. K. Oh, Y. J. Kim, H. B. Oh, and Y. J. Cho, Clin. Exp. Immunol. 123:421-427, 2001; L. Sanfilippo, C. K. Li, R. Seth, T. J. Balwin, M. J. Menozzi, and Y. R. Mahida, Clin. Exp. Immunol. 119:456-463, 2000) that purified BFT stimulates interleukin-8 (IL-8) secretion by human intestinal epithelial cells (HT29/C1 cells) and demonstrate that stimulation of IL-8 production is dependent on biologically active BFT and independent of serum. Induction of IL-8 mRNA expression occurs rapidly and ceases by 6 h after BFT treatment, whereas IL-8 secretion continues to increase for at least 18 h. Our data suggest that BFT-stimulated IL-8 secretion involves tyrosine kinase-dependent activation of nuclear factor-kappaB (NF-kappaB) as well as activation of the mitogen-activated protein kinases (MAPKs), p38 and extracellular signal-related kinase. Simultaneous activation of NF-kappaB and MAPKs appears necessary for secretion of IL-8 by HT29/C1 cells treated with BFT.

The inhibitor of apoptosis (IAP) proteins all contain one or more baculoviral IAP repeat motifs, through which they interact with various other proteins. Many IAPs also have another zinc-binding motif, the RING domain, which can recruit E2 ubiquitin-conjugating enzymes and catalyse the transfer of ubiquitin onto target proteins. The number of targets of IAP-mediated ubiquitylation is increasing and recent results indicate that outcomes following ubiquitylation are tantalizingly complex. As well as regulating other proteins, the IAPs themselves are controlled by ubiquitin-mediated degradation.