Bacteroides fragilis Enterotoxin Induces Human beta-Defensin-2 Expression in Intestinal Epithelial Cells via a Mitogen-Activated Protein Kinase/I kappa B Kinase/NF-kappa B-Dependent Pathway

Enterotoxigenic Bacteroides fragilis (ETBF) produces an approximately 20-kDa heat-labile enterotoxin (BFT) that plays an essential role in mucosal inflammation. Although spontaneous disappearance of ETBF infection is common, little information is available on regulated expression of antibacterial factors in response to BFT stimulation. This study investigates the role of BFT in human beta-defensin 2 (hBD-2) induction from intestinal epithelial cells. Stimulation of HT-29 and Caco-2 intestinal epithelial cell lines with BFT resulted in the induction of hBD-2. Activation of a reporter gene for hBD-2 was dependent on the presence of NF-kappa B binding sites. In contrast, suppression of AP-1 did not affect hBD-2 expression in BFT-stimulated cells. Inhibition of p38 mitogen-activated protein kinase (MAPK) using SB203580 and small interfering RNA (siRNA) transfection resulted in a significant reduction in BFT-induced I kappa B kinase (IKK)/NF-kappa B activation and hBD-2 expression. Our results suggest that a pathway including p38 MAPK, IKK, and NF-kappa B activation is required for hBD-2 induction in intestinal epithelial cells exposed to BFT, and may be involved in the host defense following infection with ETBF.We thank Jurgen Harder for providing hBD-2-luciferase plasmids, Martin F. Kagnoff for providing p beta-actin- and pRSV-beta-galactosidase-luciferase plasmids and standard beta-actin RNA, Andreas von Knethen for providing the dominant-negative c-Jun plasmid, and Han Jin Lee for expert technical help.; This work was supported by a National Research Foundation of Korea (NRF) grant funded by the government of Korea (MEST) (MRC program no. 2009-0091463) and by the Basic Science Research Program through the NRF funded by the Ministry of Education, Science and Technology (R11-2008-044-01004-0).; None of the authors of this study has any financial or commercial conflicts of interest