Brenne Anne-Tove, Ro Torstein Baade, Waage Anders, Sundan Anders, Borset Magne, Hjorth-Hansen Henrik
Department of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway.
Blood. 2002 May 15;99(10):3756-62. doi: 10.1182/blood.v99.10.3756.
Interleukin-21 (IL-21) is a recently cloned cytokine with homology to IL-2, IL-4, and IL-15. In this study we examined the effects of IL-21 on human myeloma cells. We found that IL-21 induced proliferation and inhibited apoptosis of the IL-6-dependent human myeloma cell lines ANBL-6, IH-1, and OH-2. The potency of IL-21 was close to that of IL-6 in the OH-2 cell line. Neutralizing antibodies to IL-6 or the IL-6 receptor transducer chain (gp130) did not affect IL-21-induced DNA synthesis, indicating that IL-21-induced proliferation was not mediated through these proteins. Tumor necrosis factor (TNF), another stimulator of myeloma cell growth, up-regulated the expression level of IL-21 receptor (IL-21R), and combinations of TNF and IL-21 gave synergistic effects on myeloma cell proliferation. Furthermore, 4 of 9 purified samples of primary myeloma cells showed a significant increase in DNA synthesis on stimulation of the cells by IL-21. By Western blot analysis, we demonstrated that the intracellular signaling pathways of IL-21 in myeloma cells involved phosphorylation of Jak1, Stat3, and Erk1/2 (p44/42 mitogen-activated protein kinase). IL-21 is a novel growth and survival factor in multiple myeloma and may represent a target for future therapy.
白细胞介素-21（IL-21）是一种最近克隆出的细胞因子，与IL-2、IL-4和IL-15具有同源性。在本研究中，我们检测了IL-21对人骨髓瘤细胞的作用。我们发现IL-21可诱导依赖IL-6的人骨髓瘤细胞系ANBL-6、IH-1和OH-2增殖并抑制其凋亡。在OH-2细胞系中，IL-21的效力与IL-6相近。针对IL-6或IL-6受体转导链（gp130）的中和抗体不影响IL-21诱导的DNA合成，这表明IL-21诱导的增殖不是通过这些蛋白介导的。肿瘤坏死因子（TNF）是骨髓瘤细胞生长的另一种刺激因子，可上调IL-21受体（IL-21R）的表达水平，TNF与IL-21联合使用对骨髓瘤细胞增殖具有协同作用。此外，在9个纯化的原发性骨髓瘤细胞样本中，有4个在IL-21刺激下DNA合成显著增加。通过蛋白质印迹分析，我们证明骨髓瘤细胞中IL-21的细胞内信号通路涉及Jak1、Stat3和Erk1/2（p44/42丝裂原活化蛋白激酶）的磷酸化。IL-21是多发性骨髓瘤中一种新的生长和存活因子，可能代表未来治疗的一个靶点。
