Bacteroides fragilis Enterotoxin Upregulates Heme Oxygenase-1 in Intestinal Epithelial Cells via a Mitogen-Activated Protein Kinase- and NF-κB-Dependent Pathway, Leading to Modulation of Apoptosis.
The Bacteroides fragilis enterotoxin (BFT), a virulence factor of enterotoxigenic B. fragilis (ETBF), interacts with intestinal epithelial cells and can provoke signals that induce mucosal inflammation. Although expression of heme oxygenase-1 (HO-1) is associated with regulation of inflammatory responses, little is known about HO-1 induction in ETBF infection. This study was conducted to investigate the effect of BFT on HO-1 expression in intestinal epithelial cells. Stimulation of intestinal epithelial cells with BFT resulted in upregulated expression of HO-1. BFT activated transcription factors such as NF-κB, AP-1, and Nrf2 in intestinal epithelial cells. Upregulation of HO-1 in intestinal epithelial cells was dependent on activated IκB kinase (IKK)-NF-κB signals. However, suppression of Nrf2 or AP-1 signals in intestinal epithelial cells did not result in significant attenuation of BFT-induced HO-1 expression. HO-1 induction via IKK-NF-κB in intestinal epithelial cells was regulated by p38 mitogen-activated protein kinases (MAPKs). Furthermore, suppression of HO-1 activity led to increased apoptosis in BFT-stimulated epithelial cells. These results suggest that a signaling pathway involving p38 MAPK-IKK-NF-κB in intestinal epithelial cells is required for HO-1 induction during exposure to BFT. Following this induction, increased HO-1 expression may regulate the apoptotic process in responses to BFT stimulation.
Department of Microbiology and Department of Biomedical Science, Hanyang University College of Medicine and Graduate School of Biomedical Science and Engineering, Seoul, South Korea.
Su Hyuk
SH
Ko
Department of Microbiology and Department of Biomedical Science, Hanyang University College of Medicine and Graduate School of Biomedical Science and Engineering, Seoul, South Korea.
Da Jeong
da J
Rho
Department of Microbiology and Department of Biomedical Science, Hanyang University College of Medicine and Graduate School of Biomedical Science and Engineering, Seoul, South Korea.
Jong Ik
JI
Jeon
Department of Biotechnology, Joongbu University, Gumsan, South Korea.
Young-Jeon
YJ
Kim
Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, South Korea.
Hyun Ae
HA
Woo
Soonchunhyang Institute of Medi-Bioscience, Soonchunhyang University, Asan, South Korea.
Yun Kyung
YK
Lee
Department of Microbiology and Department of Biomedical Science, Hanyang University College of Medicine and Graduate School of Biomedical Science and Engineering, Seoul, South Korea jungmogg@hanyang.ac.kr.
Jung Mogg
JM
Kim
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001441:Bacteroides fragilis / Q000276:immunology*; D004768:Enterotoxins / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004768:Enterotoxins; D020672:I-kappa B Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D051547:Heme Oxygenase-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases