Effects of 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid on 4-hydroxy-2-nonenal-induced apoptotic T cell death.
4-Hydroxy-2-nonenal (HNE), the aldehydic product of lipid peroxidation, is associated with multiple immune dysfunctions, such as HIV and hepatitis C virus infection. HNE-induced immunosuppression could be due to a decrease in CD4+ T lymphocyte activation or proliferation. Glutathione (GSH) is the most abundant endogenous antioxidant in cells, and an adduct between HNE and GSH has been suggested to be a marker of oxidative stress. Our earlier studies showed that HNE induced cytotoxicity and Akt inactivation, which led to the enhancement of FasL expression and concomitantly decreased cellular FLICE-like inhibitory protein (c-FLIP(S)) levels. In this study, we found that HNE caused intracellular GSH depletion in Jurkat T cells, and we further investigated the role of 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA), a GSH prodrug, in attenuating HNE-induced cytotoxicity in CD4+ T lymphocytes. The results show that PTCA protected against HNE-induced apoptosis and depletion of intracellular GSH. PTCA also suppressed FasL expression through increasing levels of Akt kinase as well as antiapoptotic c-FLIP(S) and decreasing the activation of type 2 protein serine/threonine phosphatase. Taken together, these data demonstrate a novel correlation between GSH levels and Akt activation in T lymphocyte survival, which involves FasL down-regulation and c-FLIP(S) expression through increasing intracellular GSH levels. This suggests that PTCA could potentially be used in the treatment of oxidative stress-induced immunosuppressive diseases.
Chang
Weiyuan
W
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, USA.
McClain
Craig J
CJ
Liu
Marcia C
MC
Barve
Shirish S
SS
Chen
Theresa S
TS
D000447:Aldehydes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000235:genetics; D005978:Glutathione / Q000032:analysis; D006801:Humans; D019169:Jurkat Cells; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology
D000447:Aldehydes; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D012333:RNA, Messenger; D013844:Thiazoles; D019014:fas Receptor; C101197:2-n-propylthiazolidine-4-carboxylic acid; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D005978:Glutathione; C027576:4-hydroxy-2-nonenal