Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation.
Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation.
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DOI：
10.1084/jem.177.6.1675
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发表时间：
1993-06-01
期刊：
影响因子：
--
通讯作者：
Kaplan G
中科院分区：
文献类型：
--
作者：
Moreira AL;Sampaio EP;Zmuidzinas A;Frindt P;Smith KA;Kaplan G
我们已经研究了沙利度胺抑制脂多糖（LPS）诱导的肿瘤坏死因子α（TNF-α）产生的机制，发现该药物增强TNF-α mRNA的降解。因此，在50微克/ml沙利度胺存在下，分子的半衰期从约30分钟缩短至约17分钟。对TNF-α产生的抑制是选择性的，因为其他LPS诱导的单核细胞细胞因子不受影响。已知另外两种TNF-α产生的抑制剂喷替茶碱和地塞米松通过不同的机制发挥其作用，表明这三种药物在细胞因子生物合成途径的不同点抑制TNF-α合成。这些观察结果为这些药物的协同作用提供了解释。选择性抑制TNF-α的产生使沙利度胺成为治疗炎性疾病的理想候选药物，在炎性疾病中观察到TNF-α诱导的毒性，并且免疫必须保持完整。
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.