RM, a novel resveratrol derivative, attenuates inflammatory responses induced by lipopolysaccharide via selectively increasing the Tollip protein in macrophages: A partial mechanism with therapeutic potential in an inflammatory setting

Although the novel resveratrol derivative RM has therapeutic potential for the treatment of inflammatory bowel disease, little is currently known regarding the manner whereby RM regulates excessive inflammatory responses. In this study, we initially investigated the molecular mechanisms underlying the anti-inflammatory effects induced by RM in Toll-like receptor (TLR)-activated macrophages. Upon stimulation with lipopolysaccharide, we found that RM-treated activated macrophages down-regulated the increase in pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1 beta, and IL-12p70), nitric oxide (NO) production, and activating interleukin-1 receptor-associated kinase 1 (IRAK-1) phosphorylation, mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappa B) signaling pathways. Interestingly, the TLR negative regulator Toll-interacting protein (Tollip) was selectively enhanced during RM stimulation in time- and dose-dependent manners. In response to knockdown of Tollip expression by RNA interference, RM-treated activated macrophages showed augmented expression of inflammatory mediators (pro-inflammatory cytokines, NO, inducible nitric oxidase, and cyclooxygenase-2, and surface molecules) and restored the expression of MAPK and NF-kappa B signals inhibited by RM treatment. Taken together, our findings indicate that RM has therapeutic potential for treating TLR-induced inflammatory diseases via the promotion of Tollip expression.