IL-26通过参与/调节免疫细胞、肿瘤细胞的免疫网络促进恶性胸腔积液形成的机制研究

IL-26 is a cytokine produced by immune cells that participates in a variety of inflammatory diseases through pro-inflammatory/anti-inflammatory effect, though there is no report about IL-26 participating in MPE yet. Previous studies in the project group showed the presence of IL-26 and its receptors in lung cancer and pleural metastatic lesions. Many immune cells in malignant pleural effusion (MPE) express IL-26, of which Th1 and Th17 cells may be the main source cells; exogenous TNF-α, IFN-γ, IL-22 can promote the secretion of IL-26 in peripheral blood mononuclear cells. IL-26 can promote the expression of IL-22 by Th cells in MPE, and IL-26 also has a significant effect on the apoptosis, proliferation and migration of lung cancer cells. On this basis, the project will further reveal the source of immune cells of IL-26 in MPE, the effect of tumor cells on IL-26 secretion and its mechanism, the generation/differentiation and chemotactic activity of IL-26 on lymphocyte subsets, the effects and mechanisms of IL-26 interact with human lung cancer cell lines and primary tumor cells in MPE. Furthermore, the interaction between IL-26 and immune cells, tumor cells and cytokines in MPE and the specific mechanism were explored, and the specific pathway of IL-26 involved in MPE and its effect on MPE outcome were revealed.

IL-26是一种由免疫细胞产生的细胞因子，通过促炎/抑炎作用参与多种炎症性疾病，然而尚无关于恶性胸腔积液（MPE）中IL-26作用的报道。项目组前期研究表明肺癌及胸膜转移性病灶中IL-26及其受体的表达增加。MPE中IL-26的浓度显著高于其同源外周血；其中多种免疫细胞能表达IL-26，且水平高于其同源外周血，Th1和Th17细胞可能是其主要来源细胞；外源性TNF-α、IFN-γ、IL-22能促进外周血单个核细胞分泌IL-26。此外，IL-26能通过促进MPE中CD4+T细胞以及记忆T细胞分泌IL-22参与MPE的发生发展。IL-26尚可抑制肺癌细胞的凋亡，促进其增殖、迁移。本项目将进一步深入揭示MPE中IL-26的其他免疫细胞来源，肿瘤细胞与IL-26相互作用的具体机制，IL-26对淋巴细胞亚群的发生/分化及趋化活性的影响及机制，IL-26参与MPE的具体途径及其对MPE转归的影响。

在本面上项目（81900096）研究经费的资助下，取得了如下研究成果：①与外周血（PB）相比，MPE中IL-26、IL-10和IL-6的含量升高。②在MPE中的IL-26主要由胸腔中的Th17细胞、Tc17细胞和巨噬细胞分泌。③MPE中的IL-6和IL-23可以通过磷酸化CD4+T细胞中STAT3信号通路来增加Th17谱系标记RORγt的表达从而上调IL-26的表达。④IL-26可以上调Th22细胞中Ki-67的百分比，并促进CD4+T细胞和记忆CD4+T细胞表达IL-22。⑤IL-26可以减少CD8+T细胞颗粒酶B的分泌。⑥当与肿瘤细胞共培养时，IL-26抑制了CD8+ T细胞的杀伤功能。⑦MPE中IL-26 蛋白的积累预示着患者预后差。以上结果表明，IL-26参与了MPE的发病机制，同时影响CD4+T细胞和CD8+T细胞。.项目的完成首次确定了MPE 中IL-26 的细胞来源及其分泌动力学，MPE 中IL-26 调控淋巴细胞亚群及其相应的信号通路机制以及MPE 中IL-26 与肿瘤细胞之间的相互作用及其相应的信号通路机制。项目研究成果填补了IL-26与恶性胸腔积液研究机制的空白，为MPE患者的诊断、疾病评估和治疗提供了新靶点。