3-Deazaadenosine analogues inhibit the production of tumour necrosis factor-alpha in RAW264.7 cells stimulated with lipopolysaccharide.
The effects of 3-deazaadenosine (DZA), 3-deaza(+/-)-aristeromycin (DZAri) and 3-deazaneplanocin (DZNep) on tumour necrosis factor-alpha (TNF-alpha) production were examined in the mouse macrophage cell line, RAW264.7, stimulated with lipopolysaccharide (LPS). The 3-deazaadenosine analogues inhibited the TNF-alpha production and the inhibition was dependent upon the concentration of the analogue. DZA reduced the level of TNF-alpha mRNA suggesting that DZA acts at a transcriptional step. In contrast, DZAri and DZNep had little effect on mRNA levels for TNF-alpha, implying that these compounds inhibit a post-transcriptional or translational biosynthetic step of TNF-alpha synthesis. The observation that homocysteine (Hcy) potentiated the DZA inhibition of TNF-alpha production and of TNF-alpha mRNA levels suggests that the inhibition of TNF-alpha production may be caused by elevated levels of 3-deazaadenosylhomocysteine (DZAHcy). The results show that the 3-deazaadenosine analogues are potent inhibitors of TNF-alpha 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-alpha plays an important pathogenic role.
Jeong
S Y
SY
Department of Biochemistry, Catholic University Medical College, Seoul, South Korea.
Lee
J H
JH
Kim
H S
HS
Hong
S H
SH
Cheong
C H
CH
Kim
I K
IK
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D002460:Cell Line; D003864:Depression, Chemical; D006867:Hydrolases / Q000037:antagonists & inhibitors; D007375:Interleukin-1 / Q000378:metabolism; D007536:Isomerism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014372:Tubercidin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C018258:3-deazaadenosine; C048460:3-deazaneplanocin; C034583:3-deazaaristeromycin; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine; D014372:Tubercidin