Resveratrol, a novel natural proteasome inhibitor (935.3)

Abstract

We have previously established that the cellular organelle proteasome is a central mediator of inflammation and it regulates multiple signaling pathways. Furthermore, we have also established that the chymotrypsin‐like activity of the proteasome is most important in the regulation of lipopolysaccharide (LPS)‐induced inflammation. We have recently identified resveratrol as natural inhibitor of this activity. Resveratrol is a plant‐derived natural product phytoalexin found in red grapes and other fruits, and has been reported to manifest a number of positive pharmaco‐therapeutic benefits in humans, including anti‐cancer, anti‐aging, anti‐ischemic and anti‐inflammatory properties. The mechanisms responsible for these benefits have not been studied in detail. We hypothesized that treatment of macrophages in vitro with resveratrol will block LPS‐induced, Toll‐like receptor (TLR) 4‐mediated signaling by inhibiting the activity of some proteasomal proteases, thereby inhibiting the inflammatory response. We now conclude that pretreatment of mouse macrophages in vitro with resveratrol disrupts several major TLR4‐dependent signaling pathways triggered by LPS, leading to markedly reduced secretion of several proinflammatory cytokines and nitric oxide synthase generation. Further, pretreatment of mice with resveratrol results in similar anti‐inflammatory effects in vivo. We have also shown an altered cytokine expression pattern in LPS‐stimulated human monocytes pretreated with resveratrol. Thus one of the primary mechanism(s) responsible for these reported pleiotropic effects of resveratrol on multiple cell types, and its effects on the host inflammatory system may be due to the inhibition of the proteasomal proteases. These findings will provide new opportunities for therapeutic intervention in the treatment of diseases that are based on the proteasome and have a strong inflammatory component.Grant Funding Source: Supported by NIH