IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro
IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro
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DOI：
10.1182/blood-2007-07-099531
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发表时间：
2008-05-01
期刊：
影响因子：
20.3
通讯作者：
Byrd, John C.
中科院分区：
文献类型：
--
作者：
Gowda, Aruna;Roda, Julie;Byrd, John C.
白细胞介素-21（IL-21）是新近发现的一种γ链受体细胞因子家族成员，它能促进B细胞凋亡和激活先天性免疫系统。基于此，我们推测IL-21可能增强氟达拉滨和利妥昔单抗诱导的细胞凋亡，并在增强慢性淋巴细胞白血病（CLL）细胞的免疫介导的清除中发挥作用。我们的研究表明，大多数CLL患者具有表面IL-21受体α，其表达与细胞凋亡、STAT 1的酪氨酸磷酸化和促凋亡BH 3结构域蛋白BIM的上调相关。IL-21诱导的BIM上调对于细胞凋亡至关重要，因为使用小干扰RNA抑制BIM表达阻止了IL-21诱导的细胞凋亡。用IL-21处理CLL细胞而不是正常T细胞与氟达拉滨或利妥昔单抗相加地增强了这些疗法的直接细胞毒性作用。除了其促凋亡作用外，IL-21还促进了自然杀伤细胞中STAT 1和STAT 5的磷酸化，同时增强了体外对利妥昔单抗包被的CLL细胞的抗体依赖性细胞毒性。这些数据为IL-21与氟达拉滨和利妥昔单抗在CLL中的联合研究提供了依据，并表明BIM上调可能作为相关的药效学终点来测量该细胞因子在体内的生物学效应。
Interleukin-21 (IL-21) is a recently identified gamma-chain receptor cytokine family member that promotes B-cell apoptosis as well as activation of innate immune system. Based on this, we hypothesized that IL-21 might enhance the apoptosis induced by fludarabine and rituximab and also play a role in augmenting immune-mediated clearance of the chronic lymphocytic leukemia (CLL) cells. Our studies demonstrate that the majority of CLL patients have surface IL-21 receptor-alpha, and its expression correlates with apoptosis, tyrosine phosphorylation of STAT1, and up-regulation of the proapoptotic BH3 domain protein BIM. IL-21-induced BIM up-regulation is critical for apoptosis because inhibition of BIM expression using small interfering RNA prevented IL-21-induced apoptosis. IL-21 treatment of CLL cells but not normal T cells with fludarabine or rituximab additively enhanced the direct cytotoxic effect of these therapies. In addition to its proapoptotic effect, IL-21 promoted STAT1 and STAT5 phosphorylation in natural killer cells with concurrent enhanced anti body-dependent cellular cytotoxicity against rituximab-coated CLL cells in vitro. These data provide justification for combination studies of IL-21 with fludarabine and rituximab in CLL and suggest that BIM up-regulation might serve as relevant pharmacodynamic end point to measure biologic effect of this cytokine in vivo.