Sesquiterpene Lactones Specifically Inhibit Activation of NF-κB by Preventing the Degradation of IκB-α and IκB-β

• Published in: The Journal of biological chemistry 1998-01, Vol.273 (3), p.1288-1297
• Main Authors: Hehner, Steffen P., Heinrich, Michael, Bork, Peter M., Vogt, Markus, Ratter, Frank, Lehmann, Volker, Schulze-Osthoff, Klaus, Dröge, Wulf, Schmitz, M. Lienhard
• Format: Article
• Language: English
• Subjects: Animals; DNA - metabolism; DNA-Binding Proteins - metabolism; Free Radicals; Gene Expression - drug effects; HeLa Cells; Humans; Hydrogen Peroxide - metabolism; I-kappa B Proteins; Intercellular Adhesion Molecule-1 - genetics; Jurkat Cells; Lactones - pharmacology; Mice; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Plants, Medicinal; Sesquiterpenes - pharmacology; src-Family Kinases - metabolism; Structure-Activity Relationship; Tetradecanoylphorbol Acetate - pharmacology; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.3.1288

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-κB (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-κB by different stimuli such as phorbol esters, tumor necrosis factor-α, ligation of the T-cell receptor, and hydrogen peroxide in various cell types. Treatment of cells with SLs prevented the induced degradation of IκB-α and IκB-β by all these stimuli, suggesting that they interfere with a rather common step in the activation of NF-κB. SLs did neither interfere with DNA binding activity of activated NF-κB 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-κB target gene intracellular adhesion molecule 1. Inhibition of NF-κB by SLs resulted in an enhanced cell killing of murine fibroblast cells by tumor necrosis factor-α. SLs lacking an exomethylene group in conjugation with the lactone function displayed no inhibitory activity on NF-κB. The analysis of the cellular redox state by fluorescence-activated cell sorter showed that the SLs had no direct or indirect anti-oxidant properties.