A COMPARISON OF SIGNALING REQUIREMENTS FOR APOPTOSIS OF HUMAN B-LYMPHOCYTES INDUCED BY THE B-CELL RECEPTOR AND CD95 FAS/

To define holy the signaling pathways that mediate the B cell receptor (BCR) death pathway differ from those responsible for CD95/Fas-mediat ed death, we compared the BCR and Fas death pathways in two human B ce ll Pines, B104 and BJAB. Both BCR- and Fas-induced apoptosis are block ed by the peptide cysteine protease inhibitor benzyloxycarbonyl-Val-Al a-Asp-fluoromethylketone (ZVAD (mlz)), demonstrating a common requirem ent caspase activity, Despite this common characteristic, the ability of actinomycin D and cycloheximide to block BCR-induced apoptosis, but not apoptosis induced by Fas cross-linking, suggests that a major dif ference between these two pathways is their differential requirements for new gene and protein synthesis. BCR- and Fas-mediated apoptosis ar e both accompanied by activation of stress-activated protein kinase an d p38 mitogen-activated protein kinase (MAPK), Activation of both stre ss-activated protein kinase and p38 MAPK was inhibited by ZVAD (mlz), suggesting the involvement of caspases, To determine the role of p38 M APK activation in BCR- and Fas-induced apoptosis, we employed SB203580 , a specific inhibitor of p38 MAPK. SB203580 inhibited BCR-induced apo ptosis, but not apoptosis induced by crosslinking Fas, Furthermore, bo th actinomycin D and SB203580 inhibited BCR-induced, but not Fas-induc ed, activation of caspase, Collectively, these findings establish a ro le for p38 MAPK in BCR-induced apoptosis both upstream and downstream of caspase activity. The p38 MAPK pathway may function to regulate tra nscriptional or translational events that are critical for BCR-induced apoptosis.