Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation.
We have examined the mechanism of thalidomide inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production and found that the drug enhances the degradation of TNF-alpha mRNA. Thus, the half-life of the molecule was reduced from approximately 30 to approximately 17 min in the presence of 50 micrograms/ml of thalidomide. Inhibition of TNF-alpha production was selective, as other LPS-induced monocyte cytokines were unaffected. Pentoxifylline and dexamethasone, two other inhibitors of TNF-alpha production, are known to exert their effects by means of different mechanisms, suggesting that the three agents inhibit TNF-alpha synthesis at distinct points of the cytokine biosynthetic pathway. These observations provide an explanation for the synergistic effects of these drugs. The selective inhibition of TNF-alpha production makes thalidomide an ideal candidate for the treatment of inflammatory conditions where TNF-alpha-induced toxicities are observed and where immunity must remain intact.
Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, New York 10021.
A L
AL
Moreira
E P
EP
Sampaio
A
A
Zmuidzinas
P
P
Frindt
K A
KA
Smith
G
G
Kaplan
D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D012756:Sheep; D013792:Thalidomide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D003907:Dexamethasone; D010431:Pentoxifylline