title: Crude Preparations of Helicobacter pylori Outer Membrane Vesicles Induce Upregulation of Heme Oxygenase-1 via Activating Akt-Nrf2 and mTOR-IκB Kinase-NF-κB Pathways in Dendritic Cells.
abstract: Helicobacter pylori sheds outer membrane vesicles (OMVs) that contain many surface elements of bacteria. Dendritic cells (DCs) play a major role in directing the nature of adaptive immune responses against H. pylori, and heme oxygenase-1 (HO-1) has been implicated in regulating function of DCs. In addition, HO-1 is important for adaptive immunity and the stress response. Although H. pylori-derived OMVs may contribute to the pathogenesis of H. pylori infection, responses of DCs to OMVs have not been elucidated. In the present study, we investigated the role of H. pylori-derived crude OMVs in modulating the expression of HO-1 in DCs. Exposure of DCs to crude H. pylori OMVs upregulated HO-1 expression. Crude OMVs obtained from a cagA-negative isogenic mutant strain induced less HO-1 expression than OMVs obtained from a wild-type strain. Crude H. pylori OMVs activated signals of transcription factors such as NF-κB, AP-1, and Nrf2. Suppression of NF-κB or Nrf2 resulted in significant attenuation of crude OMV-induced HO-1 expression. Crude OMVs increased the phosphorylation of Akt and downstream target molecules of mammalian target of rapamycin (mTOR), such as S6 kinase 1 (S6K1). Suppression of Akt resulted in inhibition of crude OMV-induced Nrf2-dependent HO-1 expression. Furthermore, suppression of mTOR was associated with inhibition of IκB kinase (IKK), NF-κB, and HO-1 expression in crude OMV-exposed DCs. These results suggest that H. pylori-derived OMVs regulate HO-1 expression through two different pathways in DCs, Akt-Nrf2 and mTOR-IKK-NF-κB signaling. Following this induction, increased HO-1 expression in DCs may modulate inflammatory responses in H. pylori infection.
authors.affiliation: Department of Microbiology and Department of Biomedical Science, Hanyang University College of Medicine and Graduate School of Biomedical Science and Engineering, Seoul, South Korea.
authors.forename: Su Hyuk
authors.initials: SH
authors.lastname: Ko
authors.affiliation: Department of Microbiology and Department of Biomedical Science, Hanyang University College of Medicine and Graduate School of Biomedical Science and Engineering, Seoul, South Korea.
authors.forename: Da Jeong
authors.initials: DJ
authors.lastname: Rho
authors.affiliation: Department of Microbiology and Department of Biomedical Science, Hanyang University College of Medicine and Graduate School of Biomedical Science and Engineering, Seoul, South Korea.
authors.forename: Jong Ik
authors.initials: JI
authors.lastname: Jeon
authors.affiliation: Department of Biotechnology, Joongbu University, Gumsan, South Korea.
authors.forename: Young-Jeon
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, South Korea.
authors.forename: Hyun Ae
authors.initials: HA
authors.lastname: Woo
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Jung Mogg
authors.initials: JM
authors.lastname: Kim
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism*; D000067128:Extracellular Vesicles / Q000378:metabolism*; D015870:Gene Expression; D016480:Helicobacter pylori / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D051267:NF-E2-Related Factor 2; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase