Date of Award

12-2004

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Ecology and Evolutionary Biology

Major Professor

Gary S. Sayler

Committee Members

Terry W. Schultz, James T. Fleming, Gary F. McCracken, Thomas G. Hallam

Abstract

The purpose of this study was to examine toxicity of depleted uranium (DU) to the immune system and the gene expression profile of DU-exposed immune cells including peritoneal macrophages, primary CD4+ T-cells and T Cell Hybridoma (TCH) PLP1 5B6. Flow cytometry analysis of annexin-V and Propidium Iodide (PI) binding revealed that DU causes death in those cells at various concentrations. The non-cytotoxic concentrations of DU determined in macrophages, primary CD4+ T-cells, and T cells hybridoma are 50µM, 100 µM, and 500 µM, respectively. Findings also revealed that DU-exposed macrophages are able to promote CD4+ T-cell proliferation in a concentration dependent manner.

In addition, mouse cytokine cDNA array and a confirmative method (Quantitative RT-PCR or Northern blot) were used to study the gene expression profile of DU-exposed cells. The results demonstrate that DU can modulate macrophage gene expressions such as NF-kBp65, Midkine, c-jun, and IL-10 that are related to multiple signal transduction pathways, suggesting possible involvement of DU in immune or inflammatory response, cancer development, and chronic disease. Array analysis of DU-exposed primary CD4+ T-cells reveals that DU up-regulates gene expression of a number of cytokines such as IL-5, Midkine, indicating the activities of DU in inducing cancer development, promoting eosinophil-related inflammatory diseases, and encouraging Th2 polarization. Furthermore, the possible involvement of DU in cancer development was demonstrated in TCH using microarray analysis. However, no Th2 cytokine was up-regulated in TCH after DU exposure.

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