白介素-17（IL-17）是重要的炎症因子，可能在炎症相关的肿瘤发生中发挥重要作用。我们发现肺癌通过高表达IL-17募集肿瘤相关巨噬细胞至肿瘤微环境，并在前列腺素E2作用下分化为促进肿瘤发展的M2亚型；还发现K-rasLA1小鼠肺泡重度不典型增生病灶高表达IL-17受体C，而吸入致癌剂石棉可诱导小鼠肺泡灌洗液中出现IL-17及巨噬细胞表达IL-17。根据这些发现，我们推测IL-17可能参与肺癌发生及演进。本项目将通过基因转染建立IL-17高表达小鼠模型，并利用IL-17受体C基因敲除小鼠模型，分别采用乌拉坦诱导原发性肺癌的发生，明确IL-17在肺癌发生及演进中的作用；通过IL-17抗体和TH17细胞分化抑制剂，观察抑制IL-17对肺癌发生的影响；进一步在体外、体内对肺癌细胞施加IL-17，观察IL-17对肺癌细胞的直接和间接作用，同时研究其分子、细胞机理，探索肺癌发生及演进的新机制。

Interleukin-17 (IL-17) is a critical pro-inflammatory cytokine, which may play an essential role in inflammation related carcinogenesis. Our team recently discovered that IL-17 receptor C (IL-17RC) was highly expressed in the tumor-associated macrophages (TAMs) of lung cancer. We found that TAMs in the lung cancer microenvironment were recruited by IL-17. These TAMs were induced to differentiate into the tumor-promoting M2 TAMs by prostaglandin E2. In addition, we found that IL-17RC expression was increased in alveolar hyperplasia, an early stage in lung cancer initiation, in the K-rasLA1 mouse lungs. IL-17 could also be detected in the bronchoalveolar lavage (BAL) fluid of mice after inhalation exposure to asbestos, a recognized lung carcinogen in humans. IL-17-positive alveolar macrophages could be detected in BAL after asbestos-exposure. IL-6 is an important downstream effector of IL-17 and is significantly increased in the lung of the mice post-exposure to asbestos. Based on these preliminary findings, we hypothesize that IL-17 may promote the initiation and progression of lung cancer. In order to test this hypothesis, we will make two types of animal models. One model is to over-express IL-17 in mouse lungs by adenovirus-mediated gene transfer of murine IL-17 cDNA through intra-tracheal injection. The other model is the IL-17RC gene knockout mouse. Urethane will be used to induce formation of primary lung cancers in both models. We will use these models to study the effects of IL-17 over-expression or blockade on lung cancer initiation and progression. We anticipate to identify the cellular and molecular mechanisms of how IL-17 affects the pathogenesis. Furthermore, we will test if anti-IL-17 neutralizing antibodies or inhibitors of TH17 cell can inhibit lung cancer initiation and progression in the animal models. We also propose to investigate the effects of IL-17 on lung cancer bionomics and its molecular mechanisms. This project is expected to identify new mechanisms of lung carcinogenesis, in order to develop novel methods for lung cancer prevention and treatment.