Cytoprotective function of heme oxygenase 1 induced by a nitrated cyclic nucleotide formed during murine salmonellosis

J Immunol. 2009 Mar 15;182(6):3746-56. doi: 10.4049/jimmunol.0803363.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / metabolism
  • Cyclic GMP / physiology
  • Cytoprotection / immunology*
  • Enzyme Induction / immunology
  • Enzyme Inhibitors / pharmacology
  • Heme Oxygenase-1 / antagonists & inhibitors
  • Heme Oxygenase-1 / biosynthesis
  • Heme Oxygenase-1 / physiology*
  • Liver / enzymology
  • Liver / metabolism
  • Liver / pathology
  • Macrophages, Peritoneal / enzymology
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / metabolism*
  • Nitric Oxide / physiology
  • Salmonella Infections, Animal / enzymology
  • Salmonella Infections, Animal / immunology*
  • Salmonella Infections, Animal / pathology*
  • Salmonella typhimurium / immunology
  • Signal Transduction / immunology
  • Up-Regulation / immunology


  • 8-nitroguanosine 3',5'-cyclic monophosphate
  • Enzyme Inhibitors
  • Nitric Oxide
  • Heme Oxygenase-1
  • Cyclic GMP