title: Disruption of nitric oxide signaling by Helicobacter pylori results in enhanced inflammation by inhibition of heme oxygenase-1.
abstract: A strong cellular cross-talk exists between the pathogen Helicobacter pylori and high-output NO production. However, how NO and H. pylori interact to signal in gastric epithelial cells and modulate the innate immune response is unknown. We show that chemical or cellular sources of NO induce the anti-inflammatory effector heme oxygenase-1 (HO-1) in gastric epithelial cells through a pathway that requires NF-κB. However, H. pylori decreases NO-induced NF-κB activation, thereby inhibiting HO-1 expression. This inhibitory effect of H. pylori results from activation of the transcription factor heat shock factor-1 by the H. pylori virulence factor CagA and by the host signaling molecules ERK1/2 and JNK. Consistent with these findings, HO-1 is downregulated in gastric epithelial cells of patients infected with cagA(+) H. pylori but not in gastric epithelial cells of patients infected with cagA(-) H. pylori. Enhancement of HO-1 activity in infected cells or in H. pylori-infected mice inhibits chemokine generation and reduces inflammation. These data define a mechanism by which H. pylori favors its own pathogenesis by inhibiting HO-1 induction through the action of CagA.
authors: Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors: Alain P
authors: AP
authors: Gobert
authors: Mohammad
authors: M
authors: Asim
authors: M Blanca
authors: MB
authors: Piazuelo
authors: Thomas
authors: T
authors: Verriere
authors: Brooks P
authors: BP
authors: Scull
authors: Thibaut
authors: T
authors: de Sablet
authors: Ashley
authors: A
authors: Glumac
authors: Nuruddeen D
authors: ND
authors: Lewis
authors: Pelayo
authors: P
authors: Correa
authors: Richard M
authors: RM
authors: Peek
authors: Rupesh
authors: R
authors: Chaturvedi
authors: Keith T
authors: KT
authors: Wilson
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000502:physiology*; D001426:Bacterial Proteins / Q000502:physiology*; D002460:Cell Line; D002461:Cell Line, Transformed; D005753:Gastric Mucosa / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D016480:Helicobacter pylori / Q000276:immunology* / Q000472:pathogenicity; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology*; D037521:Virulence Factors / Q000502:physiology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D018836:Inflammation Mediators; D037521:Virulence Factors; C080866:cagA protein, Helicobacter pylori; D009569:Nitric Oxide; D051547:Heme Oxygenase-1