Apoptosis of B cells upon ligation of the B cell antigen receptor (BCR) plays a role in elimination of self-reactive B cells. Previously, BCR ligation was shown to induce expression of the molecules involved in the unfolded protein response (UPR). However, the role of the UPR in BCR-mediated apoptosis is poorly understood. Here, we demonstrate that activation of various UPR molecules are induced when BCR ligation induces apoptosis in the B cell line WEHI-231 and mouse spleen B cells. BCR ligation-induced UPR is attenuated by survival signaling through CD40 in these cells. When overexpression of BiP suppresses the UPR in WEHI-231 cells, activation of p38 MAPK is blocked and apoptosis is reduced. Moreover, the p38 MAPK inhibitor SB203580 reduces BCR ligation-induced apoptosis. These results suggest that the UPR is involved in BCR ligation-induced apoptosis and that p38 MAPK is crucial for apoptosis during the UPR in B cells. (c) 2007 Elsevier Inc. All rights reserved.