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Feedback Regulation of Mitochondria by Caspase‐9 in the B Cell Receptor‐Mediated Apoptosis
Author(s) -
Eeva J.,
Nuutinen U.,
Ropponen A.,
Mättö M.,
Eray M.,
Pellinen R.,
Wahlfors J.,
Pelkonen J.
Publication year - 2009
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/j.1365-3083.2009.02331.x
Subject(s) - apoptosis , fas receptor , breakpoint cluster region , microbiology and biotechnology , biology , caspase , caspase 8 , cytochrome c , transfection , dna fragmentation , fas ligand , intrinsic apoptosis , mitochondrion , programmed cell death , receptor , cell culture , biochemistry , genetics
During the germinal centre reaction (GC), B cells with non‐functional or self‐reactive antigen receptors are negatively selected by apoptosis to generate B cell repertoire with appropriate antigen specificities. We studied the molecular mechanism of Fas/CD95‐ and B cell receptor (BCR)‐induced apoptosis to shed light on the signalling events involved in the negative selection of GC B cells. As an experimental model, we used human follicular lymphoma (FL) cell line HF1A3, which originates from a GC B cell, and transfected HF1A3 cell lines overexpressing Bcl‐x L , c‐FLIP long or dominant negative (DN) caspase‐9. Fas‐induced apoptosis was dependent on the caspase‐8 activation, since the overexpression of c‐FLIP long , a natural inhibitor of caspase‐8 activation, blocked apoptosis induced by Fas. In contrast, caspase‐9 activation was not involved in Fas‐induced apoptosis. BCR‐induced apoptosis showed the typical characteristics of mitochondria‐dependent (intrinsic) apoptosis. Firstly, the activation of caspase‐9 was involved in BCR‐induced DNA fragmentation, while caspase‐8 showed only marginal role. Secondly, overexpression of Bcl‐x L could block all apoptotic changes induced by BCR. As a novel finding, we demonstrate that caspase‐9 can enhance the cytochrome‐c release and collapse of mitochondrial membrane potential (Δ Ψ m ) during BCR‐induced apoptosis. The requirement of different signalling pathways in apoptosis induced by BCR and Fas may be relevant, since Fas‐ and BCR‐induced apoptosis can thus be regulated independently, and targeted to different subsets of GC B cells.