Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 21, 2020; 26(3): 291-306
Published online Jan 21, 2020. doi: 10.3748/wjg.v26.i3.291
Bacteroides fragilis enterotoxin upregulates heme oxygenase-1 in dendritic cells via reactive oxygen species-, mitogen-activated protein kinase-, and Nrf2-dependent pathway
Su Hyuk Ko, Jong Ik Jeon, Hyun Ae Woo, Jung Mogg Kim
Su Hyuk Ko, Jong Ik Jeon, Jung Mogg Kim, Department of Microbiology and Department of Biomedical Science, Hanyang University College of Medicine and Graduate School of Biomedical Science and Engineering, Seoul 04763, South Korea
Hyun Ae Woo, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea
Author contributions: Ko SH performed the majority of experiments and analyzed the data; Jeon JI performed the molecular investigations; Woo HA participated equally in treatment of animals; Kim JM designed and coordinated the research; Ko SH and Kim JM wrote the manuscript; all authors approved the final version of the article.
Institutional animal care and use committee statement: All animal experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee of Hanyang University and Ewha Womans University (IACUC No. 2013-0197A and IACUC No. 17-012).
Conflict-of-interest statement: None of the authors of this study has any conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Jung Mogg Kim, MD, PhD, Chairman, Director, Doctor, Professor, Department of Microbiology, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, South Korea. jungmogg@hanyang.ac.kr
Supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology, South Korea, No. NRF-2018R1D1A1B07043350.
Received: October 28, 2019
Peer-review started: October 28, 2019
First decision: December 12, 2019
Revised: December 20, 2019
Accepted: January 11, 2020
Article in press: January 11, 2020
Published online: January 21, 2020
Processing time: 79 Days and 20.6 Hours
ARTICLE HIGHLIGHTS
Research background

Enterotoxigenic Bacteroides fragilis (ETBF) causes colitis and diarrhea, and is considered a candidate pathogen in inflammatory bowel diseases as well as colorectal cancers. These diseases are dependent on ETBF-secreted toxin (BFT). Dendritic cells (DCs) play an important role in directing the nature of adaptive immune responses to bacterial infection and heme oxygenase-1 (HO-1) is involved in the regulation of DC function.

Research motivation

Although BFT can activate such transcription factor signaling in intestinal epithelial cells, there is no evidence that signals associated with BFT-induced transcription factors are related to HO-1 induction in DCs. These led us to this study.

Research objectives

The present study aimed to investigate the role of BFT in HO-1 expression in DCs.

Research methods

Murine DCs were generated from specific pathogen-free C57BL/6 and Nrf2−/− knockout mice. DCs were exposed to BFT, after which HO-1 expression and the related signaling factor activation were measured by quantitative RT-PCR, EMSA, fluorescent microscopy, immunoblot, and ELISA.

Research results

HO-1 expression was upregulated in DCs stimulated with BFT. Although BFT activated transcription factors such as NF-κB, AP-1, and Nrf2, activation of NF-κB and AP-1 was not involved in the induction of HO-1 expression in BFT-exposed DCs. Instead, upregulation of HO-1 expression was dependent on Nrf2 activation in DCs. Moreover, HO-1 expression via Nrf2 in DCs was regulated by mitogen-activated protein kinases (MAPKs) such as ERK and p38. Furthermore, BFT enhanced the production of reactive oxygen species (ROS) and inhibition of ROS production resulted in a significant decrease of phospho-ERK, phospho-p38, Nrf2, and HO-1 expression.

Research conclusions

These results suggest that signaling pathways involving ROS-mediated ERK and p38 MAPK-Nrf2 activation in DCs are required for HO-1 induction during exposure to ETBF-produced BFT.

Research perspectives

Upregulated HO-1 expression in DCs will help explain the pathogenesis of the ETBF infection. In addition, upregulated HO-1 may be an important mediator of the anti-inflammatory effects of DCs in acute ETBF infection. However, further studies are required to clarify the anti-inflammatory effects in BFT-stimulated DCs.