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We investigated the role of constitutive transcription factor nuclear factor κB (NF-κB) in nitric oxide (NO)-mediated apoptosis in J774 macrophages. Our results show that NFκB is present in untreated J774 cells in a form constitutively active. Incubation of cells with sodium nitroprusside (SNP) and S-nitroso-gluthatione (GSNO), two NO-generating compounds, caused: (a) inhibition of constitutive NF-κB/DNA binding activity; (b) decrease of cell viability; (c) DNA fragmentation; (d) ApopTag positivity. Pyrrolidine dithiocarbamate (PDTC) and N-α-para-tosyI-L-lysine chloromethyl ketone (TLCK), two inhibitors of NF-κB activation, showed the same effects of both NO-generating compounds. Furthermore, SNP and GSNO as well as PDTC and TLCK significantly increased the cytoplasmic level of IκBα. All together these results demonstrate that constitutive NF-κB protects J774 macrophages from NO-induced apoptosis. Moreover, these findings show, for the first time, that NOgenerating compounds may induce apoptosis in J774 macrophages by down-regulating constitutive NF-κB/DNA binding activity and suggest a novel mechanism by which NO induces apoptosis. [ABSTRACT FROM AUTHOR]