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

1998; Elsevier BV; Volume: 273; Issue: 3 Linguagem: Inglês

10.1074/jbc.273.3.1288

1083-351X

Steffen P. Hehner, Michael Heinrich, Peter M. Bork, Markus Vogt, Frank Ratter, Volker Lehmann, Klaus Schulze‐Osthoff, Wulf Dröge, M. Lienhard Schmitz,

Plant Toxicity and Pharmacological Properties

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.