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  • Title: The CD40-induced protection against CD95-mediated apoptosis is associated with a rapid upregulation of anti-apoptotic c-FLIP.
    Author: Eeva J, Ropponen A, Nuutinen U, Eeva ST, Mättö M, Eray M, Pelkonen J.
    Journal: Mol Immunol; 2007 Feb; 44(6):1230-7. PubMed ID: 16901543.
    Abstract:
    CD95/Fas and CD40 receptors are important regulators of cell survival during germinal center reaction. In this study we used a human follicular lymphoma cell line, HF1A3, to study molecular mechanisms of CD95-mediated apoptosis and CD40-induced rescue from apoptosis. CD95 stimulation induced activation of caspase-8 and -3, collapse of mitochondrial membrane potential (DeltaPsim), release of cytochrome c and fragmentation of nuclear DNA. All these apoptotic events were abrogated, when cells were pretreated with CD40 antibodies before CD95 stimulation. CD40 induced a rapid up regulation of both short and long isoforms of c-FLIP, as these proteins were detectable 4h after receptor stimulation. The induction of c-FLIP as well as the anti-apoptotic function of CD40 was completely abolished when NF-kappaB activity was inhibited by a selective inhibitor PDTC. We conclude that the anti-apoptotic signaling of CD40 involves NF-kappaB-mediated induction of c-FLIP proteins which can interfere with caspase-8 activation. However, it remains to be seen whether c-FLIP proteins are the only one ones involved in CD40-mediated protection.
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