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

The sedative and anti-nausea drug thalidomide, which causes birth defects i n 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 inhib ition of angio genesis. It is presently unclear whether the teratogenic pro perties of thalidomide are connected in any way to the beneficial, anti-dis ease characteristics of this drug. The transcription factor NF-kappaB has b een shown to be a key regulator of inflammatory genes such as tumor ne cros is factor-alpha and interleukin-8. Inhibition of NF-kappaB is associated wi th reduced inflammation in animal models, such as those for rheumatoid arth ritis. We show here that thalidomide can block NF-kappaB activation through a mechanism that involves the inhibition of activity of the I kappaB kinas e. Consistent with the observed inhibition of NF-kappaB, thalidomide blocke d the cytokine-induced expression of NF-kappaB-regulated genes such as thos e encoding interleukin-8, TRAF1, and c-IAP2. These data indicate that the t herapeutic potential for thalidomide may be based on its ability to block N F-kappaB activation through suppression of I kappaB kinase activity.