Selenium-containing compounds attenuate peroxynitrite-mediated NF-κB 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 κB (NF-κB) 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 (EC50 values: 8.0–13.2 μM) 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-κB 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.