title: Cytoprotective function of heme oxygenase 1 induced by a nitrated cyclic nucleotide formed during murine salmonellosis.
abstract: Signaling mechanisms of NO-mediated host defense are yet to be elucidated. In this study, we report a unique signal pathway for cytoprotection during Salmonella infection that involves heme oxygenase 1 (HO-1) induced by a nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP). Wild-type C57BL/6 mice and C57BL/6 mice lacking inducible NO synthase (iNOS) were infected with Salmonella enterica serovar Typhimurium LT2. HO-1 was markedly up-regulated during the infection, the level being significantly higher in wild-type mice than in iNOS-deficient mice. HO-1 up-regulation was associated with 8-nitro-cGMP formation detected immunohistochemically in Salmonella-infected mouse liver and peritoneal macrophages. 8-Nitro-cGMP either exogenously added or formed endogenously induced HO-1 in cultured macrophages infected with Salmonella. HO-1 inhibition by polyethylene glycol-conjugated zinc-protoporphyrin IX impaired intracellular killing of bacteria in mouse liver and in both RAW 264 cells and peritoneal macrophages. Infection-associated apoptosis was also markedly increased in polyethylene glycol-conjugated zinc-protoporphyrin IX-treated mouse liver cells and cultured macrophages. This effect of HO-1 inhibition was further confirmed by using HO-1 short interfering RNA in peritoneal macrophages. Our results suggest that HO-1 induced by NO-mediated 8-nitro-cGMP formation contributes, via its potent cytoprotective function, to host defense during murine salmonellosis.
authors.affiliation: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Mohammad Hasan
authors.initials: MH
authors.lastname: Zaki
authors.forename: Shigemoto
authors.initials: S
authors.lastname: Fujii
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okamoto
authors.forename: Sabrina
authors.initials: S
authors.lastname: Islam
authors.forename: Shahzada
authors.initials: S
authors.lastname: Khan
authors.forename: Khandaker Ahtesham
authors.initials: KA
authors.lastname: Ahmed
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sawa
authors.forename: Takaaki
authors.initials: T
authors.lastname: Akaike
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D019610:Cytoprotection / Q000276:immunology*; D004790:Enzyme Induction / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D012481:Salmonella Infections, Animal / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D012486:Salmonella typhimurium / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: C525106:8-nitroguanosine 3',5'-cyclic monophosphate; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D051547:Heme Oxygenase-1; D006152:Cyclic GMP