THALIDOMIDE EXERTS ITS INHIBITORY-ACTION ON TUMOR-NECROSIS-FACTOR-ALPHA BY ENHANCING MESSENGER-RNA DEGRADATION

We have examined the mechanism of thalidomide inhibition of lipopolysa ccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) product ion and found that the drug enhances the degradation of TNF-alpha mRNA . Thus, the half-life of the molecule was reduced from approximately 3 0 to approximately 17 min in the presence of 50 mug/ml of thalidomide. Inhibition of TNF-alpha production was selective, as other LPS-induce d monocyte cytokines were unaffected. Pentoxifylline and dexamethasone , two other inhibitors of TNF-alpha production, are known to exert the ir 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 t he synergistic effects of these drugs. The selective inhibition of TNF -alpha production makes thalidomide an ideal candidate for the treatme nt of inflammatory conditions where TNF-alpha-induced toxicities are o bserved and where immunity must remain intact.