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.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).KIM JM, 2010, LAB INVESTWu SG, 2009, NAT MED, V15, P1016, DOI 10.1038/nm.2015Sears CL, 2009, CLIN MICROBIOL REV, V22, P349, DOI 10.1128/CMR.00053-08Rhee KJ, 2009, INFECT IMMUN, V77, P1708, DOI 10.1128/IAI.00814-08Kim JM, 2009, CLIN EXP IMMUNOL, V155, P541, DOI 10.1111/j.1365-2249.2008.03849.xNuding S, 2009, MICROBES INFECT, V11, P384, DOI 10.1016/j.micinf.2009.01.001Lee JY, 2009, J MOL MED-JMM, V87, P169, DOI 10.1007/s00109-008-0415-2Sears CL, 2008, CLIN INFECT DIS, V47, P797, DOI 10.1086/591130Kim JM, 2008, EUR J IMMUNOL, V38, P2190, DOI 10.1002/eji.200838191Giesemann T, 2008, GASTROENTEROLOGY, V134, P2049, DOI 10.1053/j.gastro.2008.03.008Kim JM, 2008, LAB INVEST, V88, P541, DOI 10.1038/labinvest.2008.16Hale JD, 2007, EXPERT REV ANTI-INFE, V5, P951, DOI 10.1586/14787210.5.6.951Lee JY, 2007, J MOL MED-JMM, V85, P1393, DOI 10.1007/s00109-007-0237-7Kim JM, 2007, INFECT IMMUN, V75, P3373, DOI 10.1128/IAI.01940-06Wehkamp J, 2007, CURR OPIN GASTROEN, V23, P32Kim JM, 2006, EUR J IMMUNOL, V36, P2446, DOI 10.1002/eji.200535808Cash HL, 2006, SCIENCE, V313, P1126, DOI 10.1126/science.1127119Toprak NU, 2006, CLIN MICROBIOL INFEC, V12, P782, DOI 10.1111/j.1469-0691.2006.01494.xWehkamp K, 2006, J INVEST DERMATOL, V126, P121, DOI 10.1038/sj.jid.5700020De Smet K, 2005, BIOTECHNOL LETT, V27, P1337, DOI 10.1007/s10529-005-0936-5Kim JM, 2005, EUR J IMMUNOL, V35, P2648, DOI 10.1002/eji.200526321Schneider JJ, 2005, J MOL MED-JMM, V83, P587, DOI 10.1007/s00109-005-0657-1Sahl HG, 2005, J LEUKOCYTE BIOL, V77, P466, DOI 10.1189/jlb.0804452Wehkamp J, 2004, INFECT IMMUN, V72, P5750, DOI 10.1128/IAI.72.10.5750-5758.2004Wu SG, 2004, INFECT IMMUN, V72, P5832, DOI 10.1128/IAI.72.10.5832-5839.2004Basset C, 2004, DIGEST DIS SCI, V49, P1425Chio CC, 2004, CELL SIGNAL, V16, P565, DOI 10.1016/j.cellsig.2003.10.003Howell SJ, 2003, PEPTIDES, V24, P1763, DOI 10.1016/j.peptides.2003.07.028Park KJ, 2003, J BIOL CHEM, V278, P35272, DOI 10.1074/jbc.M305095200Tollin M, 2003, PEPTIDES, V24, P523, DOI 10.1016/S0196-9781(03)00114-1KIM JM, 2003, AM J PHYSIOL-GASTR L, V285, P1171Kim JM, 2002, CLIN EXP IMMUNOL, V130, P59Krisanaprakornkit S, 2002, J IMMUNOL, V168, P316Kim JM, 2001, CLIN EXP IMMUNOL, V123, P421Wada A, 2001, CELL MICROBIOL, V3, P115Prindiville TP, 2000, EMERG INFECT DIS, V6, P171Kim JM, 2000, SCAND J INFECT DIS, V32, P643O`Neil DA, 1999, J IMMUNOL, V163, P6718Wada A, 1999, BIOCHEM BIOPH RES CO, V263, P770Zhang GM, 1999, CLIN INFECT DIS, V29, P590Elewaut D, 1999, J IMMUNOL, V163, P1457Bals R, 1999, INFECT IMMUN, V67, P3542Kim JM, 1997, SCAND J IMMUNOL, V45, P613Niyogi SK, 1997, INDIAN J MED RES, V105, P167Eckmann L, 1996, J IMMUNOL, V156, P2894BROWN PH, 1993, ONCOGENE, V8, P877MYERS LL, 1987, AM J VET RES, V48, P774