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: Mohammad Hasan Zaki, Shigemoto Fujii, Tatsuya Okamoto, Sabrina Islam, Shahzada Khan, Khandaker Ahtesham Ahmed, Tomohiro Sawa, Takaaki Akaike
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 182 Issue 6 Pg. 3746-56 (Mar 15 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19265153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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