Inhibition of TNFa-induced activation of nuclear factor ¿B by kava (Piper methysticum) derivatives

The inducible transcription factor nuclear factor kappa B (NF-kappa B) plays a central role in the regulation of immune, inflammatory and carcinogenic responses. While normal activation of NF-kappa B 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-kappa B-driven reporter gene expression and TNF alpha-induced binding of NF-kappa B to a consensus response element was achieved at concentrations of 320 mu M (flavokavain A), 175 mu M (flavokavain B) and 870 mu M (kavain and dihydrokavain). Moreover, kavain and flavokavains A and B treatment led to inhibition of both inhibitor of kappa B (I kappa B) degradation and subsequent translocation of p50 and p65 NF-kappa B 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 I kappa B 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. (c) 2006 Elsevier Inc. All rights reserved.