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.