Thalidomide Suppresses NF-κB Activation Induced by TNF and H2O2, But Not That Activated by Ceramide, Lipopolysaccharides, or Phorbol Ester

Abstract

Thalidomide ([+]-α-phthalimidoglutarimide), a psychoactive drug that readily crosses the blood-brain barrier, has been shown to exhibit anti-inflammatory, antiangiogenic, and immunosuppressive properties through a mechanism that is not fully established. Due to the central role of NF-κB in these responses, we postulated that thalidomide mediates its effects through suppression of NF-κB activation. We investigated the effects of thalidomide on NF-κB activation induced by various inflammatory agents in Jurkat cells. The treatment of these cells with thalidomide suppressed TNF-induced NF-κB activation, with optimum effect occurring at 50 μg/ml thalidomide. These effects were not restricted to T cells, as other hematopoietic and epithelial cell types were also inhibited. Thalidomide suppressed H2O2-induced NF-κB activation but had no effect on NF-κB activation induced by PMA, LPS, okadaic acid, or ceramide, suggesting selectivity in suppression of NF-κB. The suppression of TNF-induced NF-κB activation by thalidomide correlated with partial inhibition of TNF-induced degradation of an inhibitory subunit of NF-κB (IκBα), abrogation of IκBα kinase activation, and inhibition of NF-κB-dependent reporter gene expression. Thalidomide abolished the NF-κB-dependent reporter gene expression activated by overexpression of TNFR1, TNFR-associated factor-2, and NF-κB-inducing kinase, but not that activated by the p65 subunit of NF-κB. Overall, our results clearly demonstrate that thalidomide suppresses NF-κB activation specifically induced by TNF and H2O2 and that this may contribute to its role in suppression of proliferation, inflammation, angiogenesis, and the immune system.