The novel anti-inflammatory mechanisms for phytochemicals mediated through modulation of Toll-like receptor signaling

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Toll-like receptors (TLRs) sense invading microbial pathogens and induce immune and inflammatory responses. TLRs can be activated by non-microbial endogenous molecules leading to induction of aseptic inflammation that can enhance the risk of development of many chronic inflammatory diseases including cancer. Certain phytochemicals are known to possess anti-inflammatory and chemopreventive effects. However, direct molecular targets and action mechanisms are not well understood. Therefore, we attempted to identify molecular targets of such phytochemicals in TLR signaling pathways. Curcumin and helenalin inhibited both ligand-induced and ligand-independent dimerization of TLR4 resulting in suppression of MyD88- and TRIF-dependent downstream signaling pathways. In contrast, resveratrol and (-)-epigallocatechin-3-gallate (EGCG) did not affect dimerization of TLR4, but suppressed TRIF mediated signaling pathways by inhibiting kinase activity of TBK1. While inhibitory effect of resveratrol is specific for TRIF-pathway, EGCG downregulates both MyD88- and TRIF-pathways. Together, the results showed that anti-inflammatory phytochemicals have different targets to modulate TLR-derived signaling and target gene expression, and further raise the possibility that certain dietary phytochemicals can alter susceptibility to microbial infection and the risk of chronic inflammatory diseases including cancer. [NIH-DK064007, DK41868, CA75613; USDA-2001-35200-10721; AACR-01A095Rev; WHNRC/ARS/USDA-program funds]