Phytochemicals as Modulators of Signaling in Inflammation

Abstract

Inflammatory pathways are involved in numerous chronic conditions such as arthritis, autoimmune disorders, heart disease, neurodegeneration, cancer, diabetes and obesity. Inflammation is mediated primarily by NF-κB (nuclear factor kappa-light chain-enhancer of activated B cells) in cells. NF-κB is part of a signal transduction pathway activated by surface cell receptors, stimulated by ligands such as cytokines in immune cells. This triggers the translocation of activated NF-κB into the nucleus. NF-κB then binds to DNA response elements and promotes the transcription of inflammatory proteins. During chronic conditions, gene products of NF-κB activation tend to amplify injury to bystander tissues, resulting in further localized injury. Many phytochemicals can limit this excessive cellular damage by blocking translocation of NF-κB into the nucleus. Many natural products also exert indirect control over NF-κB, such as through peroxisome proliferator activated receptor-γ (PPARγ) and liver X receptor (LXR). PPARγ and LXR are transcription factors that control lipid and cholesterol metabolism. However, the activation of PPARγ and LXR also promotes a simultaneous repression of NF-κB pathways and, hence, attenuates inflammation. A well-known class of drugs that act as gonists of PPARγ are the thiazolidinediones, used in diabetes. However, many agonists of PPARγ and LXR also consist of natural products. Thus, it may be possible to inhibit NF-κB pathways directly or stimulate PPARγ and LXR induced repression of inflammatory pathways using phytochemicals in physio-logic doses from moderate dietary intake.