一种新兴的IL-10家族细胞因子—白介素-26在结核性胸膜炎发病机制中的作用

Our previous works have provided that CD4+T lymphocytes and some cytokines are critical for the immunoregulation and development of tuberculous pleural effusion (TPE). The interleukin (IL)-10 family of cytokines has diverse roles during Mycobacterium tuberculosis (Mtb) infection ranging from immune evasion to immune protection. However, the roles of IL-26, an emerging member of the IL-10 family, in the regulation of host defense against Mtb remain poorly understood. There is only one study demonstrated the possible role of IL-26 in Mtb infection. The addition of recombinant IL-26 to whole blood infected with Mtb led to enhanced bacterial survival and growth, which is in contrast with the widely reported “microbicidal” functions of IL-26. In order to deeply explore the immunoregulation of IL-26 in TPE, we demonstrated that IL-26 was significantly higher in TPE than in blood, and the most IL-26-producing T cells were CD4+ T cells. Th1 and Th17 cells produced IL-26 and expressed IL-20R1 (receptor of IL-26). The addition of tuberculosis-specific antigen ESAT6/CFP10 to the mononuclear cells isolated from TPE led to increasing the number of IL-26-producing cell and its receptor. Our data suggest a collaborative loop between IL-26 and CD4+ T cells in pathogenesis of TPE. This study will extend our previous works and 1) will explore the cell origins and dynamics of IL-26 in TPE environment; 2) will explore the interaction regulation with IL-26 and other IL-10 family members in TPE; 3) will investigate the regulation and mechanism of IL-26 on generation, differentiation, and chemotactic activity of multiple CD4+ T cell subgroups in TPE; 4)will explore the effects and mechanism of IL-26 in TPE on biological characteristics and fibrosis of pleural mesothelium; 5) will further evaluate the clinical significance of pleural IL-26 in pathological changes, diagnosis, evaluation of therapeutic efficacy and prognosis of patients with TPE. The accomplishment of this work will elucidate the immunological activity of IL-26 in the pathogenesis of TPE, and will improve differential diagnosis and evaluation of therapeutic efficacy of TPE.

我们既往研究证实了多种CD4+T细胞和细胞因子在结核性胸膜炎(TPE)发生发展中的免疫调节作用。作为IL-10家族成员，白介素(IL)-26在结核感染免疫中的研究显著滞后。仅有的一项研究初步提示IL-26有利于结核杆菌的存活，但此结论与已广泛报道的IL-26的“杀菌”活性相悖。我们前期检测到TPE中的IL-26水平显著高于外周血，CD4+T细胞是其主要来源，其中Th1和Th17细胞均分泌IL-26并表达其受体。采用ESAT6/CFP10刺激TPE的单个核细胞显著增加IL-26+细胞数量及其受体的表达。上述结论表明IL-26参与结核免疫反应并与CD4+T细胞存在相互作用。本项目拟明确IL-26在TPE中的免疫学活性、与其它IL-10家族因子间的相互调节、对CD4+T细胞及胸膜间皮细胞增殖、分化和生物学行为的影响，以此阐明IL-26在TPE发生机制中的作用，并评估其在诊断和预后中的临床价值。

在本面上项目（81770090）研究经费的资助下，取得了如下研究成果：①在结核性胸腔积液（TPE）中表达高于外周血的IL-26主要由胸腔中Th1细胞和Th17细胞分泌，Th1细胞和Th17细胞可以在结核特异性抗原ESAT6/CFP10刺激下进一步表达IL-26；②TPE患者外周血IL-26的浓度显著高于包括恶性、感染性和漏出性胸腔积液在内的其它胸腔积液患者外周血的浓度，提示检测外周血IL-26可以用来鉴别诊断不同病因的胸腔积液；③TPE中IL-26的浓度与炎症细胞因子IL-8和TNF-α表达呈正相关关系；与临床鉴别诊断TPE的指标LDH和ADA也呈正相关关系；④IL-26促进CD4+T细胞分泌IL-22，促进了记忆性T细胞向Th22细胞分化进而参与TPE的发病过程；⑤IL-26上调了外周血中单个核细胞趋化因子CCL20和CCL22的基因表达，提示IL-26也可以促进Th22细胞向胸膜腔趋化。.项目的完成首次确定了TPE环境中合成和释放IL-26的细胞来源以及影响IL-26产生的各种因素，探讨得到IL-26对CD4+T细胞的影响及其机制，以及IL-26与其它IL-10家族细胞因子的相互调控机制，并在此基础上明确了IL-26在TPE诊断和疗效评估中的临床价值。项目研究成果填补了IL-26与人胸膜结核感染研究的空白，补充完善了IL-10家族细胞因子对结核感染免疫的调控及机制，为结核病的临床诊断及治疗工作提供了可能的新靶点。