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

Nihon Hansenbyo Gakkai Zasshi. 2009 Feb;78(1):41-7. doi: 10.5025/hansen.78.41.
[Article in Japanese]


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.

Publication types

  • Review

MeSH terms

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


  • 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