Sesquiterpene Lactones specifically inhibit activation of NF-κB by preventing the degradation of IκB-α and IκB-β
Hehner, SP, Heinrich, M, Bork, PM, Vogt, M, Ratter, F, Lehmann, V, Schulze-Osthoff, K, Droge, W & Schmitz, ML 1998, 'Sesquiterpene Lactones specifically inhibit activation of NF-κB by preventing the degradation of IκB-α and IκB-β', Journal of Biological Chemistry, vol. 273, no. 3, pp. 1288-1297.
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Extracts from certain Mexican Indian medicinal plants used in traditional indigenous medicine for the treatment of inflammations contain sequiterpene lactones (SLs), which specifically inhibit the transcription factor NF-ÎºB (Bork, P.M., Schmitz, M. L., Kuhnt, M., Escher, C., and Heinrich, M. (1997) FEBS Lett. 402, 85-90). Here we show that SLs prevented the activation of NF-ÎºB by different stimuli such as phorbol esters, tumor necrosis factor-Î±, ligation of the T-cell receptor, and hydrogen peroxide in various cell types. Treatment of cells with SLs prevented the induced degradation of IÎºB-Î± and IÎºB-Î² by all these stimuli, suggesting that they interfere with a rather common step in the activation of NF-ÎºB. SLs did neither interfere with DNA binding activity of activated NF-ÎºB nor with the activity of the protein tyrosine kinases p59(fyn) and p60(src). Micromolar amounts of SLs prevented the induced expression of the NF-ÎºB target gent intracellular adhesion molecule 1. Inhibition of NF-ÎºB by SLs resulted in an enhanced cell killing of murine fibroblast cells by tumor necrosis factor- Î±. Sis lacking an exomethylene group in conjugation with the lactone function displayed no inhibitory activity on NF-ÎºB. The analysis of the cellular redox state by fluorescence-activated cell sorter showed that the SLs had no direct or indirect anti-oxidant properties.