Inhibition of the MEK/ERK signaling pathway blocks a subset of B cell responses to antigen

Signal transduction initiated by B cell Ag receptor (BCR) cross-linking pla ys an important role in the development and activation of B cells. Therefor e, considerable effort has gone into determining the biochemical signaling events initiated by the BCR and delineating which events participate in spe cific biological responses to Ag. We used two inhibitors of mitogen-activat ed protein kinase/extracellular signal-regulated kinase kinase (MEK) 1 and MEK2, PD98059, and U0126, to assess the role the Ras-mitogen-activated prot ein kinase pathway plays in several BCR-induced responses. PD98059 or U0126 treatment substantially inhibited the BCR-induced activation of the extrac ellular signal-regulated kinase (ERK) forms of mitogen-activated protein ki nase in the immature B cell line WEBI-231, in immature splenic B cells, and in mature splenic B cells, However, MEK-ERK inhibition did not block BCR-i nduced growth arrest or apoptosis of WEHI-231 cells or apoptosis of immatur e splenic B cells, indicating that the MEK-ERK pathway is not required for these events, In contrast, PD98059 and U0126 treatment did inhibit the up-r egulation of specific BCR-induced proteins, including the transcription fac tor Egr-1 in WEHI-231 and mature splenic B cells, and the CD44 adhesion mol ecule and CD69 activation marker in mature splenic B cells. Moreover, both inhibitors suppressed BCR-induced proliferation of mature splenic B cells, in the absence and in the presence of IL-4, Therefore, activation of the ME K-ERK pathway is necessary for a subset of B cell responses to Ag.