Inhibition of TNFα-induced activation of nuclear factor κB by kava (Piper methysticum) derivatives

Abstract

The inducible transcription factor nuclear factor κB (NF-κB) plays a central role in the regulation of immune, inflammatory and carcinogenic responses. While normal activation of NF-κB 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-κB-driven reporter gene expression and TNFα-induced binding of NF-κB to a consensus response element was achieved at concentrations of 320 μM (flavokavain A), 175 μM (flavokavain B) and 870 μM (kavain and dihydrokavain). Moreover, kavain and flavokavains A and B treatment led to inhibition of both inhibitor of κB (IκB) degradation and subsequent translocation of p50 and p65 NF-κB 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 IκB 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.