Activation of cAMP signaling enhances Fas-mediated apoptosis and activation-induced cell death through potentiation of caspase 8 activation.
Defects in Fas receptor signaling lead to compromised maintenance of lymphocyte homeostasis and peripheral immune tolerance, leading in turn to autoimmune disorders. Therefore, agents that can enhance Fas-mediated apoptosis may be therapeutically useful in management of such disorders. In this study, we focused on the effect of cAMP on Fas-mediated apoptosis in human T cells. We show that elevation of intracellular cAMP levels by forskolin, an activator of adenylyl cyclase, 3-isobutyl-1-methylxanthine, an inhibitor of cyclic nucleotide phosphodiesterases, or prostaglandin E(2) potentiates Fas-induced apoptosis in Jurkat cells. Accordingly, cAMP was found to enhance the cleavage of caspase 8 at death-inducing signaling complex and lead to augmentation of the processing of Fas effector proteins. We also demonstrate that cAMP enahnaces Fas-induced apoptosis in normal human T cells and activation-induced cell death in Jurkat cells. These findings provide a rationale for investigating the feasibility of using cAMP-elevating agents to potentiate apoptosis in T cells with aberrant Fas signaling.
Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. soheil.naderi@basalmed.uio.no
Soheil
S
Naderi
Heidi Kiil
HK
Blomhoff
D000262:Adenylyl Cyclases / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D053181:Caspase 8 / Q000276:immunology / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D010835:Phytohemagglutinins / Q000494:pharmacology; D011755:Pyrophosphatases / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
D053418:Death Domain Receptor Signaling Adaptor Proteins; D010835:Phytohemagglutinins; D005576:Colforsin; D053181:Caspase 8; D011755:Pyrophosphatases; C021899:nucleotide pyrophosphatase; D000262:Adenylyl Cyclases