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)
|