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
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.