Thalidomide Exerts Its Inhibitory Action on Tumor Necrosis Factor oe by Enhancing m R N A Degradation

We have examined the mechanism of thalidomide inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor ot (TNF<~) production and found that the drug enhances the degradation of TNF-oe mRNA. Thus, the half-life of the molecule was reduced from "o30 to ~o17 rain in the presence of 50/zg/ml of thalidomide. Inhibition of TNF-ot production was selective, as other LPS-induced monocyte cytokines were unaffected. PentoxifyUine and dexamethasone, two other inhibitors of TNF-c~ production, are known to exert their effects by means of different mechanisms, suggesting that the three agents inhibit TNF-c~ 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-cr production makes thalidomide an ideal candidate for the treatment of inflammatory conditions where TNF-c~-induced toxicities are observed and where immunity must remain intact.

[1]  G. Kaplan,et al.  Prolonged treatment with recombinant interferon gamma induces erythema nodosum leprosum in lepromatous leprosy patients , 1992, The Journal of experimental medicine.

[2]  J. Walters,et al.  Increased cyclic AMP levels enhance IL-1 alpha and IL-1 beta mRNA expression and protein production in human myelomonocytic cell lines and monocytes. , 1991, The Journal of clinical investigation.

[3]  J. Norton,et al.  Pentoxifylline suppression of tumor necrosis factor gene transcription. , 1991, Surgery.

[4]  S. Zuckerman,et al.  Transcriptional and post-transcriptional mechanisms involved in the differential expression of LPS-induced IL-1 and TNF mRNA. , 1991, Immunology.

[5]  B. Beutler,et al.  Interactive effects of the tumor necrosis factor promoter and 3'-untranslated regions. , 1991, Journal of immunology.

[6]  G. Kaplan,et al.  Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes , 1991, The Journal of experimental medicine.

[7]  Jiahuai Han,et al.  Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway , 1990, The Journal of experimental medicine.

[8]  Jiahuai Han,et al.  Endotoxin-responsive sequences control cachectin/tumor necrosis factor biosynthesis at the translational level [published erratum appears in J Exp Med 1990 Mar 1;171(3):971-2] , 1990, The Journal of experimental medicine.

[9]  K. Tracey,et al.  Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia , 1989, The Journal of experimental medicine.

[10]  C. Thompson,et al.  Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. , 1989, Science.

[11]  D. Kufe,et al.  Transcriptional and posttranscriptional regulation of tumor necrosis factor gene expression in human monocytes. , 1988, The Journal of clinical investigation.

[12]  J. Mermod,et al.  Phagocytosis and inflammatory stimuli induce GM-CSF mRNA in macrophages through posttranscriptional regulation , 1987, Cell.

[13]  G. Shaw,et al.  A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation , 1986, Cell.

[14]  B. Beutler,et al.  Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. , 1986, Science.

[15]  G. Blaschke.  Chromatographic Resolution of Chiral Drugs on Polyamides and Cellulose Triacetate , 1986 .

[16]  B. Beutler,et al.  The common mediator of shock, cachexia, and tumor necrosis. , 1988, Advances in immunology.

[17]  D. Baltimore,et al.  Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. , 1986, Cell.