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Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1382-1392
CD22 Cross-Linking Generates B-Cell Antigen Receptor-Independent
Signals That Activate the JNK/SAPK Signaling Cascade
Joseph M. Tuscano,
Agostino Riva,
Salvador N. Toscano,
Thomas F. Tedder, and
John H. Kehrl
From the Department of Medicine, UC Davis Cancer Center, University
of California, Davis, Sacramento, CA; and the Department of Immunology,
Duke University Medical Center, Durham, NC.
CD22 is a B-cell-specific adhesion molecule that modulates
BCR-mediated signal transduction. Ligation of human CD22 with
monoclonal antibodies (MoAbs) that block the ligand binding site
triggers rapid tyrosine phosphorylation of CD22 and primary B-cell
proliferation. Because extracellular signal-regulated kinases (ERKs)
couple upstream signaling pathways to gene activation and are activated
by B-cell antigen receptor (BCR) signaling, we examined whether CD22
ligation also activated ERKs and/or modified BCR-induced ERK
activation. Ligation of CD22 on either primary B cells or B-cell lines
failed to significantly activate the mitogen activated protein kinase (MAPK) ERK-2, but did activate the stress-activated protein kinases (SAPKs; c-jun NH2-terminal kinases or JNKs). In contrast, BCR ligation
resulted in ERK-2 activation without significant SAPK activation.
Concurrent ligation of CD22 and BCR enhanced BCR-mediated ERK-2
activation without appreciably modulating CD22-induced SAPK activation.
Consistent with its induction of SAPK activity, there was a marked
increase in nuclear extracts of activator protein-1 (AP-1) and c-jun
levels within 2 hours of exposure of primary B cells to the CD22 MoAb.
Despite their differences in ERK activation, both CD22 and BCR ligation
triggered several Burkitt lymphoma cell lines to undergo apoptosis, and
the 2 stimuli together induced greater cell death than either signal
alone. The pro-apoptotic effects were CD22-blocking MoAb-specific and
dose-dependent. Examination of expression levels of Bcl-2 protoncogene
family members (Bcl-2, Bcl-xL, Mcl-1, and Bax) showed a
downregulation of Bcl-xL and Mcl-1 after CD22 ligation.
This study provides a plausible mechanism to explain how CD22 and BCR
signaling can costimulate B-cell proliferation and induce apoptosis in
Burkitt lymphoma cell lines.
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