Oxidized low-density lipoproteins activate CD4+ T cell apoptosis in patients with end-stage renal disease through Fas engagement.
Oxidized LDL (oxLDL) are cytotoxic to vascular cells, but their possible toxic action on T cells from patients with ESRD has not been evaluated. oxLDL concentrations were measured and compared in patients who were on long-term hemodialysis (HD), in patients who had ESRD and were on continuous ambulatory peritoneal dialysis, in nondialyzed patients with chronic kidney disease, and in age- and gender-matched control subjects. In parallel, the proliferative capacity of CD69+/CD4+ T cells and their rate of apoptosis, IL-2 expression, and intracellular expression of Bcl-2 and Bax were determined in vitro. The oxLDL concentrations were significantly higher in HD patients (all P = 0.001). Upon phytohemagglutinin stimulation, CD69+/CD4+ T cells from HD patients proliferated significantly less than those from the other patients' group (both P < 0.001). oxLDL but not the native LDL were led to CD69+/CD4+ T cells' program cell death in a dosage- and time-dependent manner through Fas pathway (P = 0.001). Cell surface Fas expression was followed by DNA fragmentation when CD69+/CD4+ T cells from HD patients or control subjects were cultured with oxLDL (200 microg/ml; 31 +/- 3 versus 25 +/- 3%; P = 0.001). In the presence of oxLDL, CD69+/CD4+ T cells from HD patients expressed significantly lower IL-2 levels, which strongly correlated with a decrease in the antiapoptotic Bcl-2 and conversely with an increase in the proapoptotic Bax expression. In conclusion, these data suggest that, in HD patients, exposure of activated CD4+ T cells to oxLDL leads to Fas-mediated apoptosis in association with inhibition of IL-2 expression. Subsequently, this may favor activation of mitochondria-dependent apoptotic pathways, leading to activated CD4+ T cell dysfunction.
Meier
Pascal
P
Service of Nephrology, Centre Hospitalier Universitaire Vaudois (CHUV), 17 rue du Bugnon, 1011 Lausanne, Suisse. pascal.meier@chuv.ch
Spertini
François
F
Blanc
Edouard
E
Burnier
Michel
M
D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D037181:Lectins, C-Type; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007376:Interleukin-2; D037181:Lectins, C-Type; D008055:Lipids; D008077:Lipoproteins, LDL; D019253:Proto-Oncogene Proteins c-bcl-2; D015375:Receptors, Interleukin-2; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D000099192:CD69 Antigens; C494826:BAX protein, human; C099252:oxidized low density lipoprotein