Inhibition of the MEK/ERK Signaling pathway Blocks a Subset of B Cell Responses to Antigen

摘要

Signal transduction initiated by B cell Ag receptor (BCR) cross-linking plays an important role in the development and activationB cells. Therefore, considerable effort has gone into determining the biochemical signaling events initiated by the BCR and~ating which events participate in specific biological responses to Ag. We used two inhibitors of mitogen-activated protein elextracellular signal-regulated kinase kinase (MEK) 1 and MEK2, PD98059, and U0126, to assess the role the Ras-mitogen-hinted protein kinase pathway plays in several BCR-induced responses. PD98059 or U0126 treatment substantially inhibited the B-induced activation of the extracellular signal-regulated kinase (ERK) forms of mitogen-activated protein kinase in the mture B cell line WEHT-231, in immature splenic B cells, and in mature splenic B cells. However, MEK-ERK inhibition did Mock BCR-induced growth arrest or apoptosis of WEHI-231 cells or apoptosis of immature splenic B cells, indicating that the ~-ERK pathway is not required for these events. In contrast, PD98059 and U0126 treatment did inhibit the up-regulation of ~ic BCR-induced proteins, including the transcription factor Egr-1 in WEHI-231 and mature splenic B cells, and the CD44 ~ion molecule and CD69 activation marker in mature splenic B cells. Moreover, both inhibitors suppressed BCR-induced iferation of mature splenic B cells, in the absence and in the presence of IL-4. Therefore, activation of the MEK-ERK pathway ~essary for a subset of B cell responses to Ag.