[New paradigm of host defense against intracellular pathogens by nitric oxide].

Abstract

Nitric oxide (NO) produced by inducible NO synthase (iNOS) during infection plays a crucial role in host defense mechanisms, via its antimicrobial and cytoprotective activities. Infection of Salmonella typhimurium in mice induces excessive production of NO, as a host defense response. We found much greater bacterial growth and apoptotic changes in iNOS-deficient (iNOS-/-) mice than in wild-type mice. However, the mechanism of NO-mediated cytoprotection during Salmonella infection remained unclear. An important signaling mechanism induced by NO is heme oxygenase (HO)-1, a significant cytoprotective molecule produced by oxidative stress. Thus, we sought to clarify NO-dependent cytoprotective and antimicrobial host defense, with a particular focus on the signaling mechanism of HO-1 induction. We recently discovered a nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), which is formed via NO possibly with reactive oxygen species. We observed strong immunoreactivity for 8-nitro-cGMP in Salmonella-infected wild-type mouse liver and peritoneal macrophages in culture but not in iNOS-/- mouse liver and macrophages. Moreover, a higher apoptosis was observed in iNOS-/- macrophages compared with wild-type macrophages after Salmonella infection, but the difference was nullified when iNOS-/- cells were treated with 8-nitro-cGMP. Finally, authentic 8-nitro-cGMP induced HO-1 in cultured macrophages infected with Salmonella. The signaling function of 8-nitro-cGMP appears to be mediated by its unique reaction with the sulfhydryl group of cysteine, thus forming a proteinS-cGMP adduct, which is an important mechanism of post-translational modification of proteins called protein S-guanylation. More importantly, we found 8-nitro-cGMP-dependent S-guanylation of Keap1, a regulatory protein of transcription factor Nrf2, which regulates the transcription of HO-1. In this review, we focus on a unique mechanism of NO-mediated host defense via formation of a novel signaling molecule, 8-nitro-cGMP in microbial infections.

• Authors: Takaaki Akaike, Tatsuya Okamoto, Md Hasan Zaki, Shigemoto Fujii, Tomohiro Sawa
• Journal: Nihon Hansenbyo Gakkai zasshi = Japanese journal of leprosy : official organ of the Japanese Leprosy Association (Nihon Hansenbyo Gakkai Zasshi) Vol. 78 Issue 1 Pg. 41-7 (Feb 2009) ISSN: 1342-3681 [Print] Japan
• PMID: 19227148 (Publication Type: Journal Article, Review)

Chemical References

• 8-nitroguanosine 3',5'-cyclic monophosphate
• Intracellular Signaling Peptides and Proteins
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• Reactive Nitrogen Species
• Reactive Oxygen Species
• Toll-Like Receptors
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Heme Oxygenase-1
• Cyclic GMP

Topics

• Animals
• Cyclic GMP (analogs & derivatives, metabolism, physiology)
• Cytoprotection
• Heme Oxygenase-1 (physiology)
• Humans
• Intracellular Signaling Peptides and Proteins (physiology)
• Kelch-Like ECH-Associated Protein 1
• Mice
• Nitric Oxide (biosynthesis, physiology)
• Nitric Oxide Synthase Type II (physiology)
• Oxidative Stress
• Reactive Nitrogen Species
• Reactive Oxygen Species
• Salmonella Infections
• Signal Transduction (physiology)
• Toll-Like Receptors (physiology)