Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells
Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells
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DOI：
10.1182/blood-2005-09-3535
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发表时间：
2006-05-01
期刊：
影响因子：
20.3
通讯作者：
Ferrini, S
中科院分区：
文献类型：
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作者：
de Totero, D;Meazza, R;Ferrini, S
白细胞介素-21（IL-21）是IL-2细胞因子家族的成员，其介导正常B细胞的增殖或生长停滞和凋亡，这取决于它们的活化状态。在这里，我们证明，表面IL-21受体（R）的表达在可变水平的慢性淋巴细胞白血病（CLL）B细胞新鲜分离自33个不同的患者。IL-21 R表达在细胞刺激后通过表面CD 40上调。因此，IL-21的作用在CD 40活化的CLL B细胞中更明显。IL-21在CLL B细胞中诱导早期信号级联，其包括JAK-1和JAK-3自磷酸化以及STAT-1、STAT-3和STAT-5的酪氨酸磷酸化。IL-21信号转导不能刺激CLL B细胞增殖，但诱导其凋亡。此外，IL-21抵消了IL-15传递给CLL B细胞的增殖和抗凋亡信号。IL-21介导的细胞凋亡涉及半胱天冬酶-8和半胱天冬酶-3的活化，Bid裂解为其活性形式t-Bid，以及PARP和p27 Kip-1的裂解。最近的数据表明，CLL B细胞需要与微环境相互作用才能生存和扩增。因此，本研究结果提供了一套新的机制，涉及在CLL B细胞的细胞存活和凋亡信号之间的平衡。
Interleukin-21 (IL-21) is a member of the IL-2 cytokine family, which mediates proliferation or growth arrest and apoptosis of normal B cells, depending on their activation state. Here we demonstrate that surface IL-21 receptor (R) is expressed at variable levels by chronic lymphocytic leukemia (CLL) B cells freshly isolated from 33 different patients. IL-21 R expression was up-regulated following cell stimulation via surface CD40. Therefore, IL-21 effects were more evident in CD40-activated CLL B cells. IL-21 induced an early signaling cascade in CLL B cells, which included JAK-1 and JAK-3 autophosphorylation and tyrosine phosphorylation of STAT-1, STAT-3, and STAT-5. IL-21 signaling failed to stimulate CLL B-cell proliferation, but induced their apoptosis. In addition, IL-21 counteracted the proliferative and antiapoptotic signals delivered by IL-15 to CLL B cells. IL-21-mediated apoptosis involved activation of caspase-8 and caspase-3, cleavage of Bid to its active form t-Bid, and cleavage of PARP and of p27Kip-1. Recent data indicate that CLL B cells require interaction with the microenvironment for their survival and expansion. The present findings thus provide a set of new mechanisms involved in the balance between cell-survival and apoptotic signals in CLL B cells.