Bcl-(xL) antagonism of BCR-coupled mitochondrial phospholipase A(2) 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 A2 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-xL. Coupling of the BCR to the mitochondrial phospholipase A2-dependent apoptotic pathway can be prevented by rescue signals via CD40. We now show that overexpression of Bcl-xL can prevent mitochondrial phospholipase A2 activation, disruption of mitochondrial potential, and postmitochondrial execution of BCR-mediated apoptosis via cathepsin B activation. Moreover, overexpression of Bcl-xL protects WEHI-231 B cells from mitochondrial disruption and apoptosis resulting from culture with exogenous arachidonic acid, the product of phospholipase A2 action, suggesting that Bcl-xL may act to antagonize arachidonic acid-mediated disruption of mitochondrial integrity. However, although Bcl-xL 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 E2 (PGE2), 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.
Katz
Elad
E
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom.
Lord
Caroline
C
Ford
Catriona A
CA
Gauld
Stephen B
SB
Carter
Natalie A
NA
Harnett
Margaret M
MM
D000818:Animals; D017209:Apoptosis; D016718:Arachidonic Acid / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism; D002401:Cathepsin B / Q000096:biosynthesis; D002460:Cell Line; D004789:Enzyme Activation; D015870:Gene Expression; D020935:MAP Kinase Signaling System; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D019013:CD40 Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D051020:bcl-X Protein; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2; D002401:Cathepsin B