Differential activation and regulation of mitogen-activated protein kinases through the antigen receptor and CD40 in human B cells

In human B cells, antigen receptor ligation and CD40 ligation are known to activate the extracellular-regulated kinases (ERK) and c-Jun N-terminal kin ase (JNK) pathways, which in turn regulate many important B cell functions. We previously reported that antigen receptor ligation activated the ERK pa thway whereas CD40 ligation activated the JNK/stress-activated protein kina se (SAPK) pathway. Here, we demonstrate that another SAPK, p38/Hog1, is act ivated by both antigen receptor ligation or CD40 ligation in a human B-lymp hoblastoid cell line and tonsillar B cells. Wortmannin, an inhibitor of pho sphatidylinositol 3-kinase, partially inhibited ERK2 and p38 activation tri ggered through the B cell receptor whereas activation of JNK1 and p38 throu gh CD40 was not affected. PD98059, a specific inhibitor of mitogen-activate d extracellular response kinase kinase (MEK), significantly inhibited ERK2 activation and partially inhibited p38 activation triggered by anti-lgM ant ibody treatment, but did not affect CD40-dependent signaling events. In add ition, anti-lgM antibody-induced signaling pathways were shown to be PKC-de pendent in contrast to the CD40-induced signaling pathways. Thus, the B cel l receptor and CD40 recruit the ERK, JNK and p38 pathways by using differen t upstream effecters.