3-Deazaadenosine, a S-Adenosylhomocysteine Hydrolase Inhibitor, Has Dual Effects on NF-κB Regulation

Previously we reported that 3-deazaadenosine (DZA), a potent inhibitor and substrate forS-adenosylhomocysteine hydrolase inhibits bacterial lipopolysaccharide-induced transcription of tumor necrosis factor-α and interleukin-1β in mouse macrophage RAW 264.7 cells. In this study, we demonstrate the effects of DZA on nuclear factor-κB (NF-κB) regulation. DZA inhibits the transcriptional activity of NF-κB 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-κB transcriptional activity is potentiated by the addition of homocysteine. Taken together, DZA promotes the proteolytic degradation of IκBα, but not IκBβ, resulting in an increase of DNA binding activity of NF-κB in the nucleus in the absence of its transcriptional activity in RAW 264.7 cells. The reduction of IκBα by DZA is neither involved in IκB 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-κB plays a central pathogenic role, as well as a useful tool for studying the regulation and physiological functions of NF-κB.

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