Damnacanthal inhibits the NF-kappa B/RIP-2/caspase-1 signal pathway by inhibiting p56(lck) tyrosine kinase

摘要

Damnacanthal is a major constituent of Morinda citrifolia L. (noni) and exhibits anti-cancer and anti-inflammatory activities. However, the effects of damnacanthal on allergic diseases have not been determined. In this study, we investigated the effect of damnacanthal on mast cell-mediated allergic inflammatory responses. Damnacanthal significantly and dose-dependently inhibited compound 48/80-induced systemic anaphylactic shock, histamine release and intracellular calcium levels. In particular, IgE-mediated passive cutaneous anaphylaxis was significantly inhibited by the oral administration of damnacanthal. In addition, we report for the first time that p56(lck) tyrosine kinase was expressed in phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-stimulated mast cells. Furthermore, damnacanthal inhibited the up-regulation of p56(lck) tyrosine kinase activity by PMACI and repressed PMACI-induced histidine decarboxylase expression and activity. Damnacanthal also inhibited PMACI-induced interleukin (IL)-1 beta, IL-6 and tumor necrosis factor-a expressions by suppressing nuclear factor-kappa B (NF-kappa B) activation and suppressed the activation of caspase-1 and the expression of receptor interacting protein-2. This study shows damnacanthal inhibits the NF-kappa B/receptor-interacting protein-2/caspase-1 signal pathway by inhibiting p56(lck) tyrosine kinase and suggests that damnacanthal has potential for the treatment of mast cell-mediated allergic disorders.