The studies presented herein examined the involvement of a p38 MAPK signaling module in B cell antigen receptor (BCR)-mediated phosphorylation and activation of CREB in the sIgM + CH31 B cell lymphoma, which undergoes Ag-dependent cell death. The activity of p38 mitogen-activated protein kinase (MAPK) was transiently increased in response to BCR ligation. Phosphorylation of CREB on serine 133, a modification which results in trans -activation, was concurrently increased. Inhibition of p38 MAPK by treatment of CH31 B cells with the pyridinyl imidazole inhibitor, SB203580, reduced BCR-induced CREB phosphorylation. Previous studies from our laboratory have identified a role for CREB in regulating junB gene expression in mature B lymphocytes; it was determined whether p38 MAPK activity was necessary for CRE-dependent junB transcription in CH31 B cells. BCR ligation led to increased junB mRNA levels, which were significantly reduced in CH31 B cells pretreated with SB203580. Activation of a CRE-dependent junB promoter/CAT reporter gene by the BCR was also abrogated by SB203580. The findings implicate a p38 MAPK pathway in BCR-mediated CREB phosphorylation and junB transcriptional activation in phenotypically immature B cell lymphomas.
CH31 B lymphomas represent a model for antigen-induced tolerance of immature B lymphocytes, because cross-linking the B cell antigen receptor (BCR) induces G 1 phase arrest and apoptosis. These data functionally characterize the role of p38 MAPK in BCR-induced apoptosis as well as evaluate the regulation of additional MAPKs by the BCR. JNK and ERK activities are not affected by BCR cross-linking. By contrast, pretreatment of CH31 B cells with the p38 MAPK inhibitor, SB203580 ablated both BCR-induced p38 MAPK activity and apoptosis. These findings establish a key role for p38 MAPK in antigen receptor-mediated apoptosis of CH31 B cells.
