Wittnebel Sebastian, Da Rocha Sylvie, Giron-Michel Julien, Jalil Abdelali, Opolon Paule, Escudier Bernard, Validire Pierre, Khawam Krystel, Chouaib Salem, Azzarone Bruno, Caignard Anne
Institut National de la Santé et de la Recherche Médicale U753, France.
Cancer Res. 2007 Jun 15;67(12):5594-9. doi: 10.1158/0008-5472.CAN-06-4406.
Renal cell carcinoma primary tumors and lung metastases are infiltrated by activated natural killer (NK) cells. Interleukin (IL)-15, a major cytokine involved in cross-talk between accessory cells (dendritic cells and macrophages) and NK cells, is produced by epithelial renal cells. We show that renal cell carcinoma cells and normal renal cells express IL-15 mRNA and membrane-bound IL-15 (MbIL-15). These cells also express IL-15 receptor alpha (IL-15Ralpha). Silencing of IL-15Ralpha by specific small interfering RNA in renal cell carcinoma had no effect on MbIL-15 production, indicating that the cytokine is not cross-presented by IL-15Ralpha in renal cell carcinoma cells but anchored to the membrane. Furthermore, we show that MbIL-15 from renal cell carcinoma cells is functional and involved in rapid nuclear translocation of phosphorylated signal transducers and activators of transcription 3 in IL-2-starved NK cells. MbIL-15 on the target did not interfere with resting NK cell activation and target cell cytolysis but rescued NK cells from IL-2 starvation-induced apoptosis through contact-dependent interaction. Masking of MbIL-15 with soluble IL-15Ralpha molecules restored NK cell apoptosis. These findings suggest that IL-15 produced by renal tumor cells is involved in the maintenance of active NK cells at the tumor site.
肾细胞癌的原发性肿瘤和肺转移灶中有活化的自然杀伤（NK）细胞浸润。白细胞介素（IL）-15是一种参与辅助细胞（树突状细胞和巨噬细胞）与NK细胞相互作用的主要细胞因子，由肾上皮细胞产生。我们发现肾癌细胞和正常肾细胞表达IL-15 mRNA和膜结合型IL-15（MbIL-15）。这些细胞还表达IL-15受体α（IL-15Rα）。在肾癌细胞中用特异性小干扰RNA沉默IL-15Rα对MbIL-15的产生没有影响，这表明该细胞因子在肾癌细胞中不是由IL-15Rα交叉呈递的，而是锚定在膜上。此外，我们发现肾癌细胞来源的MbIL-15具有功能，并且参与了IL-2饥饿的NK细胞中磷酸化信号转导子和转录激活子3的快速核转位。靶细胞上的MbIL-15不干扰静息NK细胞的激活和靶细胞的细胞溶解，但通过接触依赖性相互作用使NK细胞免受IL-2饥饿诱导的凋亡。用可溶性IL-15Rα分子封闭MbIL-15可恢复NK细胞凋亡。这些发现表明肾肿瘤细胞产生的IL-15参与了肿瘤部位活性NK细胞的维持。
