Suppression of inducible nitric oxide synthase and cyclooxygenase-2 in downregulating nuclear factor-kappa B pathway by garcinol

Garcinol is a polyisoprenylated benzophenone derivative of Garcinia indica fruit rind and other species. Recent studies have demonstrated that garcinol exhibited antioxidative effects in vitro. In this study, we found that garcinol inhibited the expression of inducible nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-activated macrophages. Western blot analyzes and gel-shift assays revealed that garcinol strongly blocks the activation of eukaryotic transcription factor nuclear factor-kappa B (NF-kappaB)-induced by LPS. Moreover, transient transfection experiments showed that garcinol inhibited the NF-kappaB-dependent transcriptional activity. Based on these data, we demonstrated that inhibition of LPS-induced NF-kappaB activation occurred through suppressing the phosphorylation of IkappaBalpha and p38 mitogen-activated kinase (MAPK). Garcinol also lowers the LPS-induced increase of intracellular reactive oxygen species (ROS), which contributes to the activation of NF-kappaB. The NF-kappaB signaling pathway leads to inflammatory reaction and our results suggest that garcinol suppresses the expression of NOS in this pathway. (C) 2004 Wiley-Liss, Inc.