An Endogenous Ah Receptor Ligand: Gene and Physiological Responses

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DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and one of a family of proteins containing the bHLH-PAS domain structure. Members of this family are involved in responding to signals in the tissue environment and serve regulatory roles in development and cellular differentiation. Although the AhR has been conserved throughout evolution and mice lacking the AhR show many defects in several organ systems, its normal function is not known. Recent work has identified an endogenous ligand, 2-(1'H-indole-3'- carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), from porcine lung and demonstrated this to be a potent AhR agonist. However, unlike toxic AhR ligands like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), ITE produces no toxicity in mice even at very high doses. It is hypothesized that ITE differentially interacts with the AhR as compared to toxic ligands such that exposure results in different molecular and biological consequences. It is also hypothesized that, based on work indicating a role of the AhR in the regulation of inflammation, that ITE may have a novel role as a regulatory molecule for inflammatory processes in the lung. Using primary mouse and human lung fibroblasts, we will rigorously determine, by microarray analyses, differences and/or similarities in the gene profile induced by ITE and TCDD. Using both isolated lung cells and a pre-clinical mouse model of lung inflammation, we will also determine whether the inflammatory response is similar or different in the presence of ITE, TCDD, or known AhR antagonists, and will begin to characterize the cellular and signaling pathways that may determine these similarities or differences. The goals of these studies are of particular significance given the wealth of data indicating a role of inflammation in the pathogenesis of several diseases including chronic obstructive pulmonary disease, hypertension, cardiovascular disease, allergic diseases such as asthma, and cancer. Understanding the role of ITE and the AhR in modulating inflammatory processes may lead to possible therapeutic interventions.