Implication of calpain in caspase activation during B cell clonal deletion

In the absence of costimulating signals, B cell receptor (BCR) crosslinking on immature B cells triggers the apoptotic cell death program. In the WEHI -231 B cell lymphoma model, anti-IgM crosslinking triggers activation of ca spase-7 independently of caspase-8, followed by apoptosis, Two main mechani sms for caspase-7 activation have been proposed: (i) caspase-8 recruitment to death receptors (Fas or tumour necrosis factor); and (ii) changes in mit ochondrial membrane permeability and cytochrome c release, which activate c aspase-9, Here we report that caspase-7 activation induced by BCR crosslink ing is independent of caspase-8 and cytochrome c translocation from mitocho ndria to the cytosol, as well as of mitochondrial depolarization. In additi on, in a cell-free system, the S-100 fraction of anti-IgM-treated WEHI-231 cells induces a caspase activation pattern different from that activated by cytochrome c and dATP, We demonstrate that calpain specifically triggers a ctivation and processing of caspase-7 both in vitro and ill vivo, and that both processes are inhibited by calpain inhibitors. Furthermore, calpain ac tivation is associated with decreased expression levels of calpastatin, whi ch is upregulated by CD40 ligation, These data confirm a role for calpain d uring BCR crosslinking, which may be critical for cell deletion by apoptosi s during B cell development and activation.