Inhibition of TNFalpha-induced activation of nuclear factor kappaB by kava (Piper methysticum) derivatives.
The inducible transcription factor nuclear factor kappaB (NF-kappaB) plays a central role in the regulation of immune, inflammatory and carcinogenic responses. While normal activation of NF-kappaB is required for cell survival and immunity, its deregulated expression is a characteristic of inflammatory and infectious diseases. In this study, we investigated the molecular mechanisms induced by lactones and chalcones isolated from Fijian kava (Piper methysticum) used in traditional medicine against urinary tract infections and asthma. In order to understand underlying regulatory mechanisms, inhibition of both NF-kappaB-driven reporter gene expression and TNFalpha-induced binding of NF-kappaB to a consensus response element was achieved at concentrations of 320 microM (flavokavain A), 175 microM (flavokavain B) and 870 microM (kavain and dihydrokavain). Moreover, kavain and flavokavains A and B treatment led to inhibition of both inhibitor of kappaB (IkappaB) degradation and subsequent translocation of p50 and p65 NF-kappaB subunits from the cytoplasm to the nucleus as shown by Western blot analysis. Additionally, kinase selectivity screening demonstrates that flavokavain A, but not kavain, nor flavokavain B, inhibits the IkappaB kinase (IKK) as well as PRAK (p38-regulated/activated kinase), MAPKAP-K3 (MAPK-activated protein kinase 3), DYRK1A (dual-specificity tyrosine-phosporylated and regulated kinase 1A) and Aurora B. Altogether, these results give a first insight into anti-inflammatory mechanisms triggered by traditionally used chemopreventive kava compounds.
Folmer
Florence
F
Marine Natural Products Laboratory, Department of Chemistry, University of Aberdeen, Scotland, UK.
Blasius
Romain
R
Morceau
Franck
F
Tabudravu
Jioji
J
Dicato
Mario
M
Jaspars
Marcel
M
Diederich
Marc
M
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression / Q000187:drug effects*; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020901:Kava / Q000737:chemistry*; D008156:Luciferases / Q000235:genetics; D015394:Molecular Structure; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D028321:Plant Preparations / Q000302:isolation & purification / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D021381:Protein Transport; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D028321:Plant Preparations; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; D051550:I-kappa B Kinase