Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Exp Hematol. 2010 May;38(5):373-83. doi: 10.1016/j.exphem.2010.02.008. Epub 2010 Mar 1.
Interleukin (IL)-21, a member of the IL-2 family, has antitumor activity and is now being tested in non-Hodgkin's lymphoma in combination with anti-CD20 antibodies. IL-21 may either induce apoptosis or promote growth in different lymphoid malignancies. We therefore investigated the IL-21/IL-21R system in follicular lymphoma (FL) cells.
IL-21R expression was studied by reverse transcription polymerase chain reaction, immunofluorescence, and Western blot analyses. Apoptosis was measured by Annexin-V-propidium iodide staining. Signaling via IL-21R was studied using antibodies specific for phosphorylated Janus-activating kinase and signal transducers and activators of transcription proteins by Western Blot.
IL-21R was found on primary FL cells in 15 of 15 cases at diagnosis and IL-21 increased apoptosis in 10 of 10 FL samples. However, cells from areas of diffuse growth in FL and from two diffuse lymphomas evolved from previous FL, showed low IL-21R expression. The latter were also resistant to IL-21-mediated apoptosis. Among lymphoma cell lines bearing the t(14;18) translocation, only 1 of 7 showed increased apoptosis in response to IL-21 stimulation. This cell line was IL-21R-positive, whereas five of six nonresponsive cell lines showed very low IL-21R expression. Intriguingly, one of the IL-21-resistant cell lines (DOHH2) expressed high levels of IL-21R. Treatment with IL-21 or IL-4 upregulated suppressor of cytokine signaling 3 gene expression in the IL-21-responsive cell line, but not in DOHH2 cells, which showed defective Janus-activating kinase/signal transducers and activators of transcription signaling in response to IL-21, in relationship to the lack of Janus-activating kinase 3 gene expression.
These data indicate that low IL-21R expression or defective signal transduction downstream IL-21R may cause refractoriness to IL-21-mediated effects in some FL cells.
白细胞介素（IL）-21 是 IL-2 家族的一员，具有抗肿瘤活性，目前正在与抗 CD20 抗体联合用于非霍奇金淋巴瘤的治疗。IL-21 可能在不同的淋巴恶性肿瘤中诱导细胞凋亡或促进其生长。因此，我们研究了滤泡性淋巴瘤（FL）细胞中的 IL-21/IL-21R 系统。
通过逆转录聚合酶链反应、免疫荧光和 Western blot 分析研究 IL-21R 的表达。通过 Annexin-V-碘化丙啶染色测量细胞凋亡。通过 Western blot 分析使用针对磷酸化 Janus 激活激酶和信号转导和转录激活蛋白的特异性抗体研究 IL-21R 信号转导。
在 15 例初诊 FL 患者的原发性 FL 细胞中均发现 IL-21R，并且 10 例 FL 样本中 IL-21 增加了细胞凋亡。然而，FL 弥漫性生长区域的细胞以及由先前 FL 演变而来的 2 例弥漫性淋巴瘤的细胞显示低 IL-21R 表达。后者也对 IL-21 介导的细胞凋亡有抵抗性。在携带 t（14;18）易位的淋巴瘤细胞系中，只有 7 例中的 1 例对 IL-21 刺激表现出增加的细胞凋亡。该细胞系 IL-21R 阳性，而 6 个无反应性细胞系中的 5 个表达非常低的 IL-21R。有趣的是，一个 IL-21 耐药细胞系（DOHH2）表达高水平的 IL-21R。用 IL-21 或 IL-4 处理可上调 IL-21 反应性细胞系中的细胞因子信号转导抑制因子 3 基因表达，但不能上调 DOHH2 细胞，后者对 IL-21 的 Janus 激活激酶/信号转导和转录激活蛋白信号传导存在缺陷，与 Janus 激活激酶 3 基因表达缺失有关。
这些数据表明，一些 FL 细胞中低 IL-21R 表达或下游 IL-21R 信号转导缺陷可能导致对 IL-21 介导的作用产生耐药性。
