Inflammation is an essential host response that serves to direct the immune system to sites of infection, but when excessive, it contributes to the pathogenesis of numerous diseases that include atherosclerosis, diabetes and cancer. Responses to microbial pathogens are initially mediated by pattern-recognition receptors that regulate the expression and activities of transcription factors that include nuclear factor B (NF-B) and interferon-regulatory factors (IRFs). These transcription factors in turn bind to specific DNA response elements on inflammatory target genes and stimulate transcription by recruiting coactivators. In addition to this activation step, recent studies indicate that the transcriptional activation of many inflammatory genes also requires a signal-dependent derepression step, involving active removal of corepressor complexes. Several members of the nuclear receptor superfamily, including the glucocorticoid receptor, peroxisome proliferator-activated receptors, and the liver X receptors, can counterregulate inflammatory responses in a ligand-dependent manner by inhibiting the formation of activator/coactivator complexes or by preventing the signal-dependent clearance of corepressor complexes. These activities influence the development of innate and adaptive immune responses to microbial infections and represent significant targets for therapeutic intervention in inflammatory diseases.
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