Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity.
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.
Keifer
J A
JA
Curriculum in Genetics and Molecular Biology, the Department of Biology, and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA.
Guttridge
D C
DC
Ashburner
B P
BP
Baldwin
A S
AS
D001483:Base Sequence; D015342:DNA Probes; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D016209:Interleukin-8 / Q000235:genetics; D019169:Jurkat Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013792:Thalidomide / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology
D015342:DNA Probes; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human