Thalidomide exerts its inhibitory action on tumor necrosis factor a by enhancing mRNA degradation

Abstract

We have examined the mechanism of thalidomide inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNF-α) production and found that the drug enhances the degradation of TNF-α mRNA. Thus, the half-life of the molecule was reduced from ∼30 to ∼17 min in the presence of 50 μg/ml of thalidomide. Inhibition of TNF-α; production was selective, as other LPS-induced monocyte cytokines were unaffected. Pentoxifylline and dexamethasone, two other inhibitors of TNF-α production, are known to exert their effects by means of different mechanisms, suggesting that the three agents inhibit TNF-α 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-α production makes thalidomide an ideal candidate for the treatment of inflammatory conditions where TNF-α-induced toxicities are observed and where immunity must remain intact.