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Cytoprotective Function of Heme Oxygenase 1 Induced by a Nitrated Cyclic Nucleotide Formed during Murine Salmonellosis¹

Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Grants-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare of Japan.

² Address correspondence and reprint requests to Prof. Takaaki Akaike, Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 860-8556 Kumamoto, Japan. E-mail address: takakaik{at}gpo.kumamoto-u.ac.jp

³ Abbreviations used in this paper: iNOS, inducible NO synthase; 8-bromo-cGMP, 8-bromoguanosine 3',5'-cyclic monophosphate; GSNO, S-nitrosoglutathione; HO-1, heme oxygenase 1; H₂-DCFDA, 2',7'-dichlorodihydrofluorescein diacetate, diacetoxymethylester; Keap1, Kelch-like ECH-associated protein 1; L-NIL, N⁶-(1-iminoethyl)-L-lysine; L-NMMA, N-monomethyl-L-arginine; MOI, multiplicity of infection; 8-nitro-cGMP, 8-nitroguanosine 3',5'-cyclic monophosphate; NOC7, 3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamine; Nrf2, NF-E2-related factor 2; PEG-ZnPP, polyethylene glycol-conjugated zinc protoporphyrin IX; RNS, reactive nitrogen oxide species; ROS, reactive oxygen species; siRNA, short interfering RNA; SNAP, S-nitroso-N-acetyl-D,L-penicillamine; 15d-PGJ₂, 15-deoxy-^12,14-PGJ₂; 8-bromo-cGMP, 8-bromoguanosine 3'5'-cyclic monophosphate.