Selenium-containing compounds attenuate peroxynitrite-mediated NF-kappaB and AP-1 activation and interleukin-8 gene and protein expression in human leukocytes.
A growing body of evidence indicates that the powerful oxidant peroxynitrite (ONOO(-)) may function as an intracellular signal for production of proinflammatory cytokines, such as interleukin-8 (IL-8) in human leukocytes. In this study, we investigated whether selenomethionine, selenocysteine, and the synthetic organoselenium compound ebselen (2-phenyl-1,2-benzisoselenazol-3(2h)-one) could inhibit ONOO(-)-mediated IL-8 gene expression in human leukocytes in whole blood. At micromolar concentrations, ebselen, selenomethionine, and selenocysteine effectively prevented nuclear accumulation of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB) evoked by exogenous ONOO(-), in both polymorphonuclear and mononuclear leukocytes, and inhibited IL-8 gene and protein expression. The inhibitory actions of selenium-containing molecules were concentration-dependent (EC(50) values: 8.0-13.2 muM) and were not shared by their sulphur analogs methionine and cystine. Furthermore, ebselen, selenomethionine, and selenocysteine markedly reduced LPS-evoked intracellular ONOO(-) formation in leukocytes, resulting in 36-66% decreases in nuclear accumulation of AP-1 and NF-kappaB in both polymorphonuclear and mononuclear leukocytes and inhibition of IL-8 mRNA expression and IL-8 release. These findings indicate that selenium-containing compounds can effectively oppose ONOO(-) signaling in leukocytes and suggest a role for selenium-containing molecules as potential modifiers of inappropriate leukocyte trafficking under pathological conditions associated with enhanced ONOO(-) formation.
Research Center, Maisonneuve-Rosemont Hospital and Department of Medicine, University of Montréal, Montréal, Québec, Canada.
Levente
L
József
János G
JG
Filep
D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018036:Selenium Compounds / Q000494:pharmacology* / Q000633:toxicity; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D018036:Selenium Compounds; D018808:Transcription Factor AP-1; D030421:Peroxynitrous Acid