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  • 标题:Heme Oxygenase and Carbon Monoxide: Medicine Chemistry and Biological Effects Guest Editor: Yuji Naito A New Paradigm for Antimicrobial Host Defense Mediated by a Nitrated Cyclic Nucleotide
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  • 作者:Tatsuya Okamoto ; Shahzada Khan ; Kohta Oyama
  • 期刊名称:Journal of Clinical Biochemistry and Nutrition
  • 印刷版ISSN:0912-0009
  • 电子版ISSN:1880-5086
  • 出版年度:2010
  • 卷号:46
  • 期号:1
  • 页码:14-19
  • DOI:10.3164/jcbn.SR09-70
  • 出版社:The Society for Free Radical Research Japan
  • 摘要:Nitric oxide (NO), produced by inducible NO synthase (iNOS) during infection, plays a crucial role in host defense mechanisms. Salmonella typhimurium infection in mice is associated with excessive production of NO from iNOS as a host defense response. An important cytoprotective and antimicrobial function of NO is mediated by induction of heme oxygenase (HO)-1. The signaling mechanism of NO-dependent HO-1 induction has remained unclear, however. We recently discovered a nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), which is formed via guanine nitration with NO and reactive oxygen species. iNOS-dependent 8-nitro-cGMP formation and HO-1 induction were identified in Salmonella -infected mice. Extensive apoptosis observed with iNOS-deficient macrophages infected with Salmonella was remarkably suppressed via HO-1 induced by 8-nitro-cGMP formed in cells. This cytoprotective signaling appears to be mediated by the reaction of 8-nitro-cGMP with protein sulfhydryls to generate a novel post-translational modification named protein S -guanylation. We also found that 8-nitro-cGMP specifically S -guanylates Keap1, a negative regulator of transcription factor Nrf2, which in turn up-regulates transcription of HO-1. Here, we discuss the unique mechanism of NO-mediated host defense that operates via formation of a novel signaling molecule - 8-nitro-cGMP - during microbial infections.
  • 关键词:nitric oxide;host defense;8-nitro-cGMP;heme oxygenase-1;protein S-guanylation
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