Involvement of stress-activated protein kinase and p38 mitogen-activated protein kinase in mIgM-induced apoptosis of human B lymphocytes

Despite intensive efforts, the intracellular signaling pathways that mediate apoptosis remain unclear. The human B lymphoma cell line, B104, possesses characteristics that make it an attractive model for analysis of receptor-mediated apoptosis. Although these cells express both membrane IgM (mIgM) and membrane IgD (mIgD) crosslinking mIgM results in significant apoptosis while crosslinking mIgD does not. Our results show that crosslinking mIgM but not mIgD induced a delayed and sustained activation of the mitogen-activated protein kinase (MAPK) family members stress-activated protein kinase (SAPK) and p38 MAPK. The calcium ionophore ionomycin, which also induces apoptosis in B104 cells, stimulated a similar SAPK and p38 MAPK response. Cyclosporin A, a potent inhibitor of apoptosis induced by either mIgM or ionomycin, inhibited activation of both SAPK and p38 MAPK, suggesting that stimulation of these kinases may be required for induction of apoptosis. Collectively, our results indicate that SAPK and p38 MAPK may be downstream targets during mIgM-induced, calcium-mediated, apoptosis in human B lymphocytes.

尽管学界已开展大量深入研究，但介导细胞凋亡的胞内信号通路仍未完全阐明。人B淋巴瘤细胞系B104具备多项特性，使其成为研究受体介导细胞凋亡的理想模型。该细胞系同时表达膜免疫球蛋白M（membrane IgM，mIgM）与膜免疫球蛋白D（membrane IgD，mIgD），但交联mIgM可诱导显著的细胞凋亡，而交联mIgD则无此效应。本研究结果显示，仅交联mIgM（而非mIgD）可诱导丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）家族成员应激活化蛋白激酶（stress-activated protein kinase, SAPK）与p38 MAPK出现延迟且持续的激活。钙离子载体离子霉素（ionomycin）同样可诱导B104细胞发生凋亡，其引发的SAPK与p38 MAPK激活模式与mIgM交联诱导的结果相似。环孢素A（Cyclosporin A）是一种可有效抑制mIgM交联或离子霉素诱导的细胞凋亡的抑制剂，它同时阻断了SAPK与p38 MAPK的激活，这提示激活这两类激酶可能是细胞凋亡诱导过程中的必要环节。综上，本研究结果表明，在人B淋巴细胞中，SAPK与p38 MAPK可能是mIgM诱导、钙离子介导的细胞凋亡通路中的下游靶标。