title: Helicobacter bilis gamma-glutamyltranspeptidase enhances inflammatory stress response via oxidative stress in colon epithelial cells.
abstract: Helicobacter bilis (H. bilis) infection is associated with cases of inflammatory bowel Disease, thyphlocolitis, hepatitis and cholecystitis. However, little is known about the bacterial virulence determinants or the molecular mechanisms involved. Recently, H. bilis γ-glutamyltranspeptidase (HBgGT) was shown to be a virulence factor decreasing host cell viability. Bacterial gGTs play a key role in synthesis and degradation of glutathione and enables the bacteria to utilize extracellular glutamine and glutathione as sources of glutamate. gGT-mediated loss of cell viability has so far been linked to DNA damage via oxidative stress, but the signaling cascades involved herein have not been described. In this study, we identified enhanced ROS production induced by HBgGT as a central factor involved in the activation of the oxidative stress response cascades, which finally activate CREB, AP-1 and NF-κB in H. bilis infected colon cancer cells. IL-8, an important pro-inflammatory chemokine that is a common downstream target of these transcription factors, was up-regulated upon H. bilis infection in an HBgGT dependent manner. Moreover, the induction of these signaling responses and inflammatory cytokine production in host cells could be linked to HBgGT-mediated glutamine deprivation. This study implicates for the first time HBgGT as an important regulator of signaling cascades regulating inflammation in H. bilis infected host epithelial cells that could be responsible for induction of inflammatory disorders by the bacterium.
authors.affiliation: Department of Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.
authors.forename: Sundus
authors.initials: S
authors.lastname: Javed
authors.forename: Raquel
authors.initials: R
authors.lastname: Mejías-Luque
authors.forename: Behnam
authors.initials: B
authors.lastname: Kalali
authors.forename: Christian
authors.initials: C
authors.lastname: Bolz
authors.forename: Markus
authors.initials: M
authors.lastname: Gerhard
mesh_terms: D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism* / Q000382:microbiology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D016998:Helicobacter / Q000201:enzymology*; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D016209:Interleukin-8; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D005973:Glutamine; D005723:gamma-Glutamyltransferase