Graduate Thesis Or Dissertation
 

Direct effects of 2,3,7,8 tetrachlorodibenzo-p-dioxin on antigen-presenting cells and molecular signaling pathways in dendritic cells

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  • In experimentally exposed mice, the environmental contaminant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) produces significant suppression of adaptive immune responses at low doses. However, the underlying biochemical and cellular mechanisms of TCDD-induced immunotoxicity have remained elusive since the identification of these effects nearly 30 years ago. Antigen-presenting cells (APC) constitute various populations of cells essential for the initiation and maintenance of adaptive immune responses, and represent a potential target of TCDD toxicity. Thus, the studies presented here address the ability of TCDD to directly affect APC. The underlying objectives of these studies focus on the investigation of molecular signaling pathways and cellular processes potentially affected by TCDD. In order to eliminate conflicting variables found in vivo, we used ex vivo and in vitro models to address these objectives. Initial studies investigated the status and behavior of the aryl hydrocarbon receptor (AhR), a transcription factor recognized as the principal mediator of TCDD-induced immunotoxic effects, in the two main APC populations, macrophages and dendritic cells (DC). The results demonstrated that both APC populations expressed AhR. However, TCDD induced binding of AhR to dioxin response elements only in macrophages, and not DC. Because TCDD has been shown to alter DC function and survival in vivo, the possibility that TCDD altered other signaling pathways was addressed. Specifically, activation of the transcription factor NF-kB/Rel, integral in DC generation and function, was found to be suppressed by TCDD. This suppression was apparently mediated by a physical association between the AhR and proteins of NF-kB/Rel. Additional studies demonstrated that TCDD enhances the maturation of DC and appears to sensitize DC to apoptosis. These data establish that TCDD directly affects DC on the molecular and cellular levels and support several potential mechanisms of TCDD-induced immunotoxicity.
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