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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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. AIM To investigate the role of BFT in HO-1 expression in DCs. 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. 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 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. CONCLUSION These results suggest that signaling pathways involving ROS-mediated ERK and p38 mitogen-activated protein kinases-Nrf2 activation in DCs are required for HO-1 induction during exposure to ETBF-produced BFT.

Original languageEnglish
Pages (from-to)291-306
Number of pages16
JournalWorld Journal of Gastroenterology
Volume26
Issue number8
DOIs
StatePublished - 2020 Jan 21

Keywords

  • Bacteroides fragilis enterotoxin
  • Dendritic cells
  • Heme oxygenase-1
  • Mitogen-activated protein kinases
  • Nrf2
  • Signaling

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