ARYL HYDROCARBON RECEPTOR AND NF-KAPPAB INTERACTIONS

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Many studies have demonstrated that aryl hydrocarbon receptor (AhR) agonists, including polynuclear aromatic hydrocarbons (PAH) that are ubiquitously distributed in the environment, adversely affect the immune system. Epidemiological analysis of human populations exposed to AhR agonists revealed multi-faceted immune dysfunction in those individuals. Studies in the Sherr laboratory have shown that PAH rapidly induce apoptosis in murine bone marrow stromal cell-dependent preB cells. The preB cell "death signal" was shown to be produced by the stromal cells by an AhR-dependent mechanism. Initial studies have shown that PAH activate NF-kappaB-DNA binding in bone marrow stromal cells and suggested that NF-kappaB also may participate in the pathway leading to production of the "death signal." Therefore, the specific aims of this study were developed to address the hypothesis that AhR agonists alter the NF-kappaB signaling pathway in bone marrow stromal cells, resulting in adverse biological responses potentially including the production of the preB cell "death signal." We will: 1) determine how NF-kappaB is modulated by a model PAH/AhR agonist in bone marrow stromal cells, 2) define PAH-mediated alterations in the kinase signaling cascade upstream of NF-kappaB, and 3) define requirements for AhR-p65 association and transcriptional activity.