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. / Graduation date: 2002
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/32558 |
| Date | 19 November 2001 |
| Creators | Ruby, Carl E. |
| Contributors | Kerkvliet, Nancy I. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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