Assessing bioflavonoids as regulators of NF-κB activity and inflammatory gene expression in mammalian cells

Inflammation is a multifactorial response that is of fundamental importance in the maintenance of cellular homeostasis when the organism is challenged by noxious agents (e.g., bacteria, viruses, parasites) or by tissue mechanical injury. Inflammatory processes are associated with a dramatic rise in the number of polymorphonuclear leukocytes and monocytes in the affected tissue and the subsequent release of various molecules such as prostaglandins and cytokines. Under ideal conditions, inflammation results in the complete recovery of the integrity of the affected tissue. However, if the response of the triggering stimulus is not subjected to a tight regulation, a condition known as chronic inflammation can be established. Indeed, a chronic inflammatory-like environment characterizes the pathogenesis of various diseases, such as atheriosclerosis, rheumatoid arthritis,and Crohn's disease, and is thought to be among the causative factor of more than 30% of human cancer.1 The transcription factor NF-KB, in cooperation with others, has been suggested to coordinate the expression of genes encoding proteins that are involved in inflammatory processes. In particular, NF-KB contributes to the production of interleukin (IL)-I, IL-6, tumor necrosis factor (TNF)-et, lymphotoxin, GM-CSF, and interferon (IFN)-~. Furthermore, some of these cytokines, e.g., IL-1 and TNFa, activate NF-KB themselves, thus initiating an autoregulatory feedback loop. 2 NF-KB activation by various stimuli occurs on its dissociation from the inhibitory protein I-KB and its subsequent nuclear translocation. Several lines of evidence, including the inhibition by various antioxidants, suggest that NF-KB activity is subject to redox regulation. 3 Because of the pivotal role in inflammatory response a significant effort has focused on developing therapeutic agents that regulate NFKB activity.