Date on Master's Thesis/Doctoral Dissertation

5-2006

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Committee Chair

Chen, Theresa S.

Subject

Oxidative stress; Immunology

Abstract

Oxidative stress-induced immunosuppression could be due to a decrease in CD4 + T lymphocyte activation or proliferation. 4-Hydroxynonenal (HNE), an end product of lipid peroxidation, and its protein adducts act as markers of oxidative stress. In this study, the effects of HNE on a human CD4 + Jurkat T cells were examined. Systematic determinations of the effects of HNE on cytotoxicity, Akt and protein phosphatase 2A(PP2A) activation, Fas/FasL-mediated apoptotic signaling, methionine adenosyltransferase (MAT) II activity, MAT 2A and c-Myb expression and cellular glutathione (GSH) and S-adenosylmethionine (SAMe) levels were performed. The results showed that HNE induced cytotoxicity, downregulated Akt and upregulated PP2A activation, and resulted in enhanced FasL expression, death-inducing signaling complex (DISC) formation, Fas-associated death domain (FADD) recruitment, and caspases cleavages, and comitantly decreased c-FLIP S expression. Further, HNE-induced cytotoxicity and lost of survival is associated with GSH depletion in a threshold phenomena and can be potentiated by inhibition of GSH synthesis. In addition, HNE toxicity was also involved with SAMe metabolism by inhibition of MAT II activity, MAT 2A and c-Myb expression and which resulted in decreases in SAMe concentrations and lead to caspase-3 dependent apoptosis. 2(RS)- n -propylthiazolidine-4( R )-carboxylic acid (PTCA), a GSH precursor, restored GSH and SAMe as well as upregulated Akt and MAT activities, protected against HNE toxicity. It was concluded that HNE toxicity may be due to an Akt regulated, Fas/FasL-mediated, and caspase-8 dependent apoptotic signaling pathway, that HNE toxicity is associated with GSH depletion and can be prevented by a GSH precursor, and that MAT and SAMe may be involved in HNE toxicity.

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