Inhibition of the MEK/ERK signaling pathway blocks a subset of B cell responses to antigen
Inhibition of the MEK/ERK signaling pathway blocks a subset of B cell responses to antigen
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DOI：
10.4049/jimmunol.166.6.3855
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发表时间：
2001-03-15
影响因子：
4.4
通讯作者：
DeFranco, AL
中科院分区：
文献类型：
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作者：
Richards, JD;Davé, SH;DeFranco, AL
由B细胞抗原受体(BCR)交联启动的信号转导在B细胞的发育和激活中起着重要作用。因此，在确定由BCR启动的生化信号事件和描绘哪些事件参与对Ag的特定生物反应方面已经做出了相当大的努力。我们使用了两种丝裂原活化蛋白激酶/细胞外信号调节激酶(MEK)1和MEK2的抑制剂，PD98059和U0126，来评估Ras丝裂原活化蛋白激酶通路在BCR诱导的几种反应中所起的作用。PD98059或U0126处理显著抑制了BCR诱导的未成熟B细胞系WEBI-231、未成熟B细胞和成熟B细胞中细胞外信号调节蛋白激酶(ERK)的激活，但MEK-ERK抑制并未阻止BCR诱导的WEHI-231细胞的生长停滞或凋亡或未成熟B细胞的凋亡，表明MEK-ERK通路不是这些事件所必需的，相反，PD98059和U0126处理确实抑制了BCR诱导的特定蛋白的上调，包括WEHI-231和成熟B细胞中的转录因子Egr-1成熟脾B细胞CD44黏附分子和CD69活化标志物。此外，在没有和存在IL-4的情况下，这两种抑制剂都抑制了BCR诱导的成熟B细胞的增殖，因此，MEK-ERK通路的激活是B细胞对抗原的一种亚群反应所必需的。
Signal transduction initiated by B cell Ag receptor (BCR) cross-linking plays an important role in the development and activation of B cells. Therefore, considerable effort has gone into determining the biochemical signaling events initiated by the BCR and delineating which events participate in specific biological responses to Ag. We used two inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) 1 and MEK2, PD98059, and U0126, to assess the role the Ras-mitogen-activated protein kinase pathway plays in several BCR-induced responses. PD98059 or U0126 treatment substantially inhibited the BCR-induced activation of the extracellular signal-regulated kinase (ERK) forms of mitogen-activated protein kinase 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-induced growth arrest or apoptosis of WEHI-231 cells or apoptosis of immature 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-regulation of specific BCR-induced proteins, including the transcription factor Egr-1 in WEHI-231 and mature splenic B cells, and the CD44 adhesion molecule 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 MEK-ERK pathway is necessary for a subset of B cell responses to Ag.