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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