SESQUITERPENE LACTONES SPECIFICALLY INHIBIT ACTIVATION OF NF-KAPPA-B BY PREVENTING THE DEGRADATION OF I-KAPPA-B-ALPHA AND I-KAPPA-B-BETA

Extracts from certain Mexican Indian medicinal plants used in traditio nal indigenous medicine for the treatment of inflammations contain seq uiterpene lactones (SLs), which specifically inhibit the transcription factor NF-kappa B (Bork, P. M., Schmitz, M. L., Kuhnt, M., Escher, C. , and Heinrich, M. (1997) FEES Lett. 402, 85-90). Here we show that SL s prevented the activation of NF-kappa B by different stimuli such as phorbol esters, tumor necrosis factor-alpha, ligation of the T-cell re ceptor, and hydrogen peroxide in various cell types. Treatment of cell s with SLs prevented the induced degradation of I kappa B-alpha and I kappa B-beta by all these stimuli, suggesting that they interfere with a rather common step in the activation of NF-kappa B. SLs did neither interfere with DNA binding activity of activated NF-kappa B nor with the activity of the protein tyrosine kinases p59(fyn) and p60(src). Mi cromolar amounts of SLs prevented the induced expression of the NF-kap pa B target gene intracellular adhesion molecule 1. Inhibition of NF-k appa B by SLs resulted in an enhanced cell killing of murine fibroblas t cells by tumor necrosis factor-alpha. SLs lacking an exomethylene gr oup in conjugation with the lactone function displayed no inhibitory a ctivity on NF-kappa B. The analysis of the cellular redox state by flu orescence-activated cell sorter showed that the SLs had no direct or i ndirect anti oxidant properties.