Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity

• Published in: The Journal of biological chemistry Vol. 276; no. 25; p. 22382
• Main Authors: Keifer, J A, Guttridge, D C, Ashburner, B P, Baldwin, Jr, A S
• Format: Journal Article
• Language: English
• Published: United States 22-06-2001
• Subjects: Base Sequence; DNA Probes; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; Humans; I-kappa B Kinase; Interleukin-1 - antagonists & inhibitors; Interleukin-1 - physiology; Interleukin-8 - genetics; Jurkat Cells; NF-kappa B - antagonists & inhibitors; NF-kappa B - biosynthesis; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Thalidomide - pharmacology; Transcription, Genetic - drug effects; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0021-9258

The sedative and anti-nausea drug thalidomide, which causes birth defects in humans, has been shown to have both anti-inflammatory and anti-oncogenic properties. The anti-inflammatory effect of thalidomide is associated with suppression of cytokine expression and the anti-oncogenic effect with inhibition of angiogenesis. It is presently unclear whether the teratogenic properties of thalidomide are connected in any way to the beneficial, anti-disease characteristics of this drug. The transcription factor NF-kappaB has been shown to be a key regulator of inflammatory genes such as tumor necrosis factor-alpha and interleukin-8. Inhibition of NF-kappaB is associated with reduced inflammation in animal models, such as those for rheumatoid arthritis. We show here that thalidomide can block NF-kappaB activation through a mechanism that involves the inhibition of activity of the IkappaB kinase. Consistent with the observed inhibition of NF-kappaB, thalidomide blocked the cytokine-induced expression of NF-kappaB-regulated genes such as those encoding interleukin-8, TRAF1, and c-IAP2. These data indicate that the therapeutic potential for thalidomide may be based on its ability to block NF-kappaB activation through suppression of IkappaB kinase activity.