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

A b s t r a c tAlthough