3-deazaadenosine analogues inhibit the production of tumour necrosis factor-α in RAW264.7 cells stimulated with lipopolysaccharide

Abstract

The effects of 3-deazaadenosine (DZA), 3-deaza(±)-aristeromycin (DZAri) and 3-deazaneplanocin (DZNep) on tumour necrosis factor-α (TNF-α) production were examined in the mouse macrophage cell line, RAW264.7, stimulated with lipopolysaccharide (LPS). The 3-deazaadenosine analogues inhibited the TNF-α production and the inhibition was dependent upon the concentration of the analogue. DZA reduced the level of TNF-α mRNA suggesting that DZA acts at a transcriptional step. In contrast, DZAri and DZNep had little effect on mRNA levels for TNF-α, implying that these compounds inhibit a post-transcriptional or translational biosynthetic step of TNF-α synthesis. The observation that homocysteine (Hcy) potentiated the DZA inhibition of TNF-α production and of TNF-α mRNA levels suggests that the inhibition of TNF-α production may be caused by elevated levels of 3-deazaadenosylhomocysteine (DZAHcy). The results show that the 3-deazaadenosine analogues are potent inhibitors of TNF-α production in the RAW264.7 cell line stimulated with LPS and suggest that these analogues may be effective agents for the treatment of diseases in which TNF-α plays an important pathogenic role.