3-deazaadenosine, a S-adenosylhomocysteine hydrolase inhibitor, has dual effects on NF-κB regulation -: Inhibition of NF-κB transcriptional activity and promotion of IκBα degradation

Previously we reported that 3 deazaadenosine (DZA), a potent inhibitor and substrate for 3-adenosylhomocysteine hydrolase inhibits bacterial lipopolysaccharide-induced transcription of tumor necrosis factor-alpha and interleukin-1 beta in mouse macrophage RAW 264.7 cells. In this study, we demonstrate the effects of DZA on nuclear factor-kappa B (NF-kappa B) regulation. DZA inhibits the transcriptional activity of NF-kappa B through the hindrance of p65 (Rel-A) phosphorylation without reduction of its nuclear translocation and DNA binding activity. The inhibitory effect of DZA on NF-kappa B transcriptional activity is potentiated by the addition of homocysteine. Taken together, DZA promotes the proteolytic degradation of I kappa B alpha, but not I kappa B beta, resulting in an increase of DNA binding activity of NF-kappa B in the nucleus in the absence of its transcriptional activity in RAW 264.7 cells. The reduction of I kappa B alpha by DZA is neither involved in I kappa B kinase complex activation nor modulated by the addition of homocysteine. This study strongly suggests that DZA may be a potent drug for the treatment of diseases in which NF-kappa B plays a central pathogenic role, as well as a useful tool for studying the regulation and physiological functions of NF-kappa B.