Craxton Andrew, Draves Kevin E, Gruppi Adriana, Clark Edward A
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
J Exp Med. 2005 Nov 21;202(10):1363-74. doi: 10.1084/jem.20051283.
The B cell activating factor belonging to the tumor necrosis factor family (BAFF) is required for B cell survival and maturation. The mechanisms by which BAFF mediates B cell survival are less understood. We found that BAFF and a proliferation-inducing ligand (APRIL), which are related, block B cell antigen receptor (BCR)-induced apoptosis upstream of mitochondrial damage, which is consistent with a role for Bcl-2 family proteins. BCR ligation strongly increased expression of the proapoptotic Bcl-2 homology 3-only Bcl-2 protein Bim in both WEHI-231 and splenic B cells, and increases in Bim were reversed by BAFF or APRIL. Small interfering RNA vector-mediated suppression of Bim blocked BCR-induced apoptosis. BAFF also induced Bim phosphorylation and inhibited BCR-induced association of Bim with Bcl-2. BAFF induced delayed but sustained stimulation of extracellular signal-regulated kinase (ERK) and its activators, mitogen-activated protein kinase/ERK activating kinase (MEK) and c-Raf, and MEK inhibitors promoted accumulation and dephosphorylation of Bim. These results suggest that BAFF inhibits BCR-induced death by down-regulating Bim via sustained ERK activation, demonstrating that BAFF directly regulates Bim function. Although transitional immature type 1 (T1) B cell numbers are normal in Bim(-/-) mice, T2 and follicular mature B cells are elevated and marginal zone B cells are reduced. Our results suggest that mature B cell homeostasis is maintained by BAFF-mediated regulation of Bim.
肿瘤坏死因子家族的B细胞活化因子（BAFF）是B细胞存活和成熟所必需的。BAFF介导B细胞存活的机制尚不清楚。我们发现，相关的BAFF和增殖诱导配体（APRIL）在线粒体损伤上游阻断B细胞抗原受体（BCR）诱导的凋亡，这与Bcl-2家族蛋白的作用一致。BCR连接在WEHI-231细胞和脾B细胞中均强烈增加促凋亡的仅含Bcl-2同源结构域3的Bcl-2蛋白Bim的表达，而BAFF或APRIL可逆转Bim的增加。小干扰RNA载体介导的Bim抑制可阻断BCR诱导的凋亡。BAFF还诱导Bim磷酸化，并抑制BCR诱导的Bim与Bcl-2的结合。BAFF诱导细胞外信号调节激酶（ERK）及其激活剂丝裂原活化蛋白激酶/ERK激活激酶（MEK）和c-Raf的延迟但持续的刺激，而MEK抑制剂促进Bim的积累和去磷酸化。这些结果表明，BAFF通过持续的ERK激活下调Bim来抑制BCR诱导的死亡，表明BAFF直接调节Bim功能。尽管在Bim基因敲除小鼠中过渡性未成熟1型（T1）B细胞数量正常，但T2和滤泡成熟B细胞数量增加，边缘区B细胞数量减少。我们的结果表明，成熟B细胞的稳态是由BAFF介导的Bim调节维持的。
