Zhang Yang, Liu Ye, Xu Yuechao
Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, China.
Intensive Care Unit, 964th Hospital of PLA, Changchun, China.
Front Oncol. 2019 Dec 10;9:1401. doi: 10.3389/fonc.2019.01401. eCollection 2019.
Interleukin (IL)-24 plays a potential anti-tumor activity in colorectal cancer in a dose-dependent manner. However, the immunoregulatory role of IL-24 to peripheral and tumor-infiltrating T cell function in colorectal cancer was not fully elucidated. In this study, twenty-nine colorectal adenocarcinoma patients and fifteen healthy individuals were enrolled. IL-24 expression and IL-24 receptor (IL-20R1, IL-20R2, and IL-22R1) mRNA relative level was measured by ELISA and real-time PCR, respectively. CD4 and CD8 T cells were purified from peripheral bloods and cancer specimens, and were stimulated with low (10 ng/ml) and high (100 ng/ml) concentration of recombinant IL-24. CD4 T cells activity was assessed by measurement of Th cell percentage, transcriptional factors, and cytokine production. CD8 T cells activity was evaluated by investigation of cytotoxic molecules, target cell death, and interferon-γ (IFN-γ) secretion. IL-24 was decreasingly expressed in both peripheral bloods and cancer tissues in colorectal adenocarcinoma patients. However, IL-20R1 and IL-20R2 was comparable between healthy controls and colorectal adenocarcinoma patients. Low concentration of IL-24 suppressed CD4 T cell proliferation. In contrast, high concentration of IL-24 not only promoted CD4 T cell proliferation, but also enhanced CD4 T cell activity, which mainly presented as up-regulation of Th1/Th17 frequency, T-bet/RORγt mRNA, and IFN-γ/IL-17 production but down-regulation of Treg percentage, FoxP3 mRNA, and IL-10/IL-35 secretion. Moreover, high concentration of IL-24 also increased perforin and granzyme B expression in CD8 T cells, and elevated cytolytic and non-cytolytic activity of CD8 T cells, which presented as induction of target cell death and elevation of IFN-γ expression. However, low concentration of IL-24 did not affect bioactivity of CD8 T cells. The current data indicated that IL-24 might regulate T cell function in a dose-dependent manner. High-concentration of IL-24 might promote anti-tumor immune responses in development novel therapeutic approaches to colorectal adenocarcinoma.
白细胞介素（IL）-24在结直肠癌中以剂量依赖的方式发挥潜在的抗肿瘤活性。然而，IL-24对结直肠癌外周血及肿瘤浸润T细胞功能的免疫调节作用尚未完全阐明。本研究纳入了29例结直肠腺癌患者和15名健康个体。分别采用酶联免疫吸附测定（ELISA）和实时聚合酶链反应（PCR）检测IL-24表达及IL-24受体（IL-20R1、IL-20R2和IL-22R1）mRNA相对水平。从外周血和癌组织标本中纯化CD4和CD8 T细胞，并用低浓度（10 ng/ml）和高浓度（100 ng/ml）的重组IL-24进行刺激。通过检测Th细胞百分比、转录因子和细胞因子产生来评估CD4 T细胞活性。通过研究细胞毒性分子、靶细胞死亡和干扰素-γ（IFN-γ）分泌来评估CD8 T细胞活性。IL-24在结直肠腺癌患者的外周血和癌组织中均呈递减表达。然而，健康对照与结直肠腺癌患者之间IL-20R1和IL-20R2水平相当。低浓度的IL-24抑制CD4 T细胞增殖。相反，高浓度的IL-24不仅促进CD4 T细胞增殖，还增强CD4 T细胞活性，主要表现为Th1/Th17频率、T-bet/RORγt mRNA以及IFN-γ/IL-17产生上调，而调节性T细胞（Treg）百分比、FoxP3 mRNA以及IL-10/IL-35分泌下调。此外，高浓度的IL-24还增加了CD8 T细胞中穿孔素和颗粒酶B的表达，并提高了CD8 T细胞的溶细胞和非溶细胞活性，表现为诱导靶细胞死亡和IFN-γ表达升高。然而，低浓度的IL-24不影响CD8 T细胞的生物学活性。目前的数据表明，IL-24可能以剂量依赖的方式调节T细胞功能。高浓度的IL-24可能在开发结直肠腺癌新治疗方法中促进抗肿瘤免疫反应。
