title: Sesquiterpene lactones specifically inhibit activation of NF-kappa B by preventing the degradation of I kappa B-alpha and I kappa B-beta.
abstract: 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-kappa B (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-kappa B by different stimuli such as phorbol esters, tumor necrosis factor-alpha, ligation of the T-cell receptor, and hydrogen peroxide in various cell types. Treatment of cells 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 p59fyn and p60arc. Micromolar amounts of SLs prevented the induced expression of the NF-kappa B target gene intracellular adhesion molecule 1. Inhibition of NF-kappa B by SLs resulted in an enhanced cell killing of murine fibroblast cells by tumor necrosis factor-alpha. SLs lacking an exomethylene group in conjugation with the lactone function displayed no inhibitory activity on NF-kappa B. The analysis of the cellular redox state by fluorescence-activated cell sorter showed that the SLs had no direct or indirect anti-oxidant properties.
authors.affiliation: Department of Immunochemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S P
authors.initials: SP
authors.lastname: Hehner
authors.forename: M
authors.initials: M
authors.lastname: Heinrich
authors.forename: P M
authors.initials: PM
authors.lastname: Bork
authors.forename: M
authors.initials: M
authors.lastname: Vogt
authors.forename: F
authors.initials: F
authors.lastname: Ratter
authors.forename: V
authors.initials: V
authors.lastname: Lehmann
authors.forename: K
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: W
authors.initials: W
authors.lastname: Dröge
authors.forename: M L
authors.initials: ML
authors.lastname: Schmitz
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005609:Free Radicals; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020672:I-kappa B Proteins; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D019169:Jurkat Cells; D007783:Lactones / Q000494:pharmacology*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010946:Plants, Medicinal; D012717:Sesquiterpenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D005609:Free Radicals; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007783:Lactones; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D006861:Hydrogen Peroxide; D019061:src-Family Kinases; D013755:Tetradecanoylphorbol Acetate