Thalidomide suppresses NF-κB activation induced by TNF and H2O2, but not that activated by ceramide, lipopolysaccharides, or phorbol ester

Thalidomide ([+]-alpha-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-KB in these responses, we postulated that thalidomide mediates its effects through suppression of NF-KB activation. We investigated the effects of thalidomide on NF-KB activation induced by various inflammatory agents In Jurkat cells. The treatment of these cells with thalidomide suppressed TNF-induced NF-kB activation, with optimum effect occurring at 50 mug/ml thalidomide. These effects were not restricted to T cells, as other hematopoletic and epithelial cell types were also inhibited. Thalidomide suppressed H2O2-induced NF-kB activation but had no effect on NF-kB activation induced by PMA, LIPS, okadaic acid, or ceramide, suggesting selectivity in suppression of NF-kB. The suppression of TNF-induced NF-kB activation by thalidomide correlated with partial inhibition of TNF-induced degradation of an inhibitory subunit of NF-KB (1kBalpha), abrogation of IkBalpha kinase activation, and inhibition of NF-kB-dependent reporter gene expression. Thalidomide abolished the NF-kB-dependent reporter gene expression activated by overexpression of TNFR1, TNFR-associated factor-2, and NF-kB-inducing kinase, but not that activated by the p65 subunit of NF-KB. Overall, our results clearly, demonstrate that thalidomide suppresses NF-KB 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.