Cytoprotective function of heme oxygenase 1 induced by a nitrated cyclic nucleotide formed during murine salmonellosis.
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.
Zaki
Mohammad Hasan
MH
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Fujii
Shigemoto
S
Okamoto
Tatsuya
T
Islam
Sabrina
S
Khan
Shahzada
S
Ahmed
Khandaker Ahtesham
KA
Sawa
Tomohiro
T
Akaike
Takaaki
T
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
C525106:8-nitroguanosine 3',5'-cyclic monophosphate; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D051547:Heme Oxygenase-1; D006152:Cyclic GMP