New paradigm of host defense against intracellular pathogens by nitric oxide

Takaaki Akaike, Tatsuya Okamoto, Hasan Md Zaki, Shigemoto Fujii, Tomohiro Sawa

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 protein- S-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.

Original languageEnglish (US)
Pages (from-to)41-47
Number of pages7
JournalJapanese Journal of Leprosy
Volume78
Issue number1
DOIs
StatePublished - 2009

Fingerprint

Nitric Oxide
Heme Oxygenase-1
Nitric Oxide Synthase
Macrophages
Salmonella Infections
Protein S
Salmonella
Infection
Cytoprotection
Liver
Cyclic Nucleotides
Peritoneal Macrophages
Nitric Oxide Synthase Type II
Salmonella typhimurium
Post Translational Protein Processing
8-nitroguanosine 3',5'-cyclic monophosphate
Cysteine
Reactive Oxygen Species
Oxidative Stress
Transcription Factors

Keywords

  • 8-Nitro-cGMP
  • Heme oxygenase-1
  • Host defense
  • Nitric oxide
  • Oxidative stress

ASJC Scopus subject areas

  • Dermatology
  • Infectious Diseases

Cite this

New paradigm of host defense against intracellular pathogens by nitric oxide. / Akaike, Takaaki; Okamoto, Tatsuya; Zaki, Hasan Md; Fujii, Shigemoto; Sawa, Tomohiro.

In: Japanese Journal of Leprosy, Vol. 78, No. 1, 2009, p. 41-47.

Research output: Contribution to journalArticle

Akaike, Takaaki ; Okamoto, Tatsuya ; Zaki, Hasan Md ; Fujii, Shigemoto ; Sawa, Tomohiro. / New paradigm of host defense against intracellular pathogens by nitric oxide. In: Japanese Journal of Leprosy. 2009 ; Vol. 78, No. 1. pp. 41-47.
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AB - 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 protein- S-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.

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