Bcl-xL antagonism of BCR-coupled mitochondrial phospholipase A2 signaling correlates with protection from apoptosis in WEHI-231 B cells

Crosslinking of the antigen receptors on the immature B-cell lymphoma, WEHI-231, leads to growth arrest and apoptosis. Commitment to such B-cell receptor (BCR)-mediated apoptosis correlates with mitochondrial phospholipase, A(2) activation, disruption of mitochondrial function, and cathepsin B activation. CD40 signaling has been reported to rescue WEHI-231 B cells from BCR-driven apoptosis primarily via up-regulation of the antiapoptotic protein Bcl-x(L). Coupling of the BCR to the mitochondrial phospholipase A(2)-dependent apoptotic pathway can be prevented by rescue signals via CD40. We now show that overexpression of Bcl-x(L) can prevent mitochondrial phospholipase A(2) activation, disruption of mitochondrial potential, and postmitochondrial execution of BCR-mediated apoptosis via cathepsin B activation. Moreover, overexpression of Bcl-x(L) protects WEHI-231 B cells from mitochondrial disruption and apoptosis resulting from culture with exogenous arachidonic acid, the product of phospholipase A(2) action, suggesting that Bcl-x(L) may act to antagonize arachidonic acid-mediated disruption of mitochondrial integrity. However, although Bcl-x(L) expression can mimic CD40-mediated rescue of BCR-driven apoptosis, it cannot substitute for CD40 signaling in the reversal of BCR-mediated growth arrest of WEHI-231 B cells. Rather, CD40 signaling additionally induces conversion of arachidonic acid to prostaglandin E-2 (PGE(2)), which promotes WEHI-231 B-cell proliferation by restoring the sustained, cycling extracellular signal-regulated/mitogen-activated protein kinase (ErkMAPkinase) signaling required for cell cycle progression.