Herrin Brantley R, Justement Louis B
Division of Developmental and Clinical Immunology, Department of Microbiology, University of Alabama, Birmingham, 35294, USA.
J Immunol. 2006 Apr 1;176(7):4163-72. doi: 10.4049/jimmunol.176.7.4163.
Analysis of hematopoietic Src homology 2 (HSH2) protein expression in mouse immune cells demonstrated that it is expressed at low levels in resting B cells but not T cells or macrophages. However, HSH2 expression is up-regulated within 6-12 h in response to multiple stimuli that promote activation, differentiation, and survival of splenic B cells. HSH2 expression is increased in response to anti-CD40 mAb, the TLR ligands LPS and CpG DNA, and B lymphocyte stimulator (BLyS), a key regulator of peripheral B cell survival and homeostasis. Stimulation of B cells with anti-CD40 mAb, LPS, CpG DNA, or BLyS has previously been shown to induce activation of NF-kappaB. In agreement with this finding, up-regulation of HSH2 expression in response to these stimuli is blocked by inhibitors of NF-kappaB activation and is potentiated by stimulation with PMA, suggesting that HSH2 expression is dependent on NF-kappaB activation. In contrast to CD40, BAFF receptor, TLR4, and TLR9 mediated signaling, stimulation of splenic B cells via the BCR was not observed to induce expression of HSH2 unless the cells had been stimulated previously through CD40. Finally, HSH2 expression is down-regulated in splenic B cells in response to stimulation with IL-21, which has been shown to induce apoptosis, even in the presence of anti-CD40 mAb, LPS, or CpG DNA. IL-21 stimulation also results in down-regulation of antiapoptotic proteins such as Bcl-x(L) and up-regulation of proapoptotic proteins like Bim. Therefore, HSH2 expression is coordinately up-regulated with known antiapoptotic molecules and directly correlates with B cell survival.
对小鼠免疫细胞中造血Src同源2（HSH2）蛋白表达的分析表明，它在静息B细胞中低水平表达，而在T细胞或巨噬细胞中不表达。然而，在多种促进脾B细胞激活、分化和存活的刺激下，HSH2表达在6 - 12小时内上调。HSH2表达在抗CD40单克隆抗体、Toll样受体配体LPS和CpG DNA以及B淋巴细胞刺激因子（BLyS，外周B细胞存活和稳态的关键调节因子）作用下增加。先前已证明用抗CD40单克隆抗体、LPS、CpG DNA或BLyS刺激B细胞可诱导NF-κB激活。与此发现一致，这些刺激下HSH2表达的上调被NF-κB激活抑制剂阻断，并被佛波酯刺激增强，表明HSH2表达依赖于NF-κB激活。与CD40、BAFF受体、TLR4和TLR9介导的信号传导相反，除非细胞先前已通过CD40刺激，否则未观察到通过BCR刺激脾B细胞诱导HSH2表达。最后，脾B细胞中HSH2表达在IL-21刺激下下调，IL-21已被证明可诱导凋亡，即使存在抗CD40单克隆抗体、LPS或CpG DNA。IL-21刺激还导致抗凋亡蛋白如Bcl-x(L)下调和促凋亡蛋白如Bim上调。因此，HSH2表达与已知抗凋亡分子协同上调，并与B细胞存活直接相关。
