Expression of membrane-bound and soluble FasL in Fas- and FADD-dependent T lymphocyte apoptosis induced by mildly oxidized LDL.
Apoptosis plays an essential role in atherosclerosis. Oxidized low-density lipoproteins (oxLDL) and activated T lymphocytes are present in atherosclerotic lesions, and we have previously reported that oxLDL induce apoptosis of activated T lymphocytes. We now show that this is preceded by an increase of Fas and FasL expression. Fas and FasL overexpression was dependent on reactive oxygen species (ROS) production as well as ERK and JNK activation. In addition, oxLDL triggered an early production of soluble FasL by T lymphocytes. Blocking anti-Fas antibody or Fas-Fc protein, but also antioxidant molecules and inhibitors of ERK and JNK, decreased oxLDL-mediated apoptosis. Moreover, PHA-activated murine lymphocytes lacking a functional Fas receptor were partially resistant to oxLDL. Finally, Jurkat T cells deficient for FADD, an adaptor protein required for Fas signaling, resisted oxLDL-induced apoptosis. OxLDL triggered caspase 8 and 3 activation as well as ceramide production in PHA-activated lymphocytes and in Jurkat cells. Caspase activation was completely impaired in FADD-deficient cells, but ceramide production was not affected. Altogether, our results highlight the putative role of both membrane-bound and soluble FasL in oxLDL-induced Fas and FADD-dependent apoptosis of T lymphocytes and suggest an involvement of ROS, ERK, and JNK in this process.
Alcouffe
Julie
J
INSERM U466, CHU Rangueil, 1 Avenue Jean Poulhès, TSA 50032 31059 Toulouse Cedex 9, France.
Therville
Nicole
N
Ségui
Bruno
B
Nazzal
Dani
D
Blaes
Nelly
N
Salvayre
Robert
R
Thomsen
Mogens
M
Benoist
Hervé
H
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D002352:Carrier Proteins / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D019169:Jurkat Cells; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002518:Ceramides; C505533:FADD protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D019014:fas Receptor; C099252:oxidized low density lipoprotein; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases