Department of Gastrointestinal Surgery, College of Life Sciences, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
Adv Sci (Weinh). 2021 Oct;8(19):e2101501. doi: 10.1002/advs.202101501. Epub 2021 Aug 8.
The balance between antioxidants and reactive oxygen species (ROS) critically regulates tumor initiation and progression. However, whether and how the tumor-favoring redox status is controlled by cytokine networks remain poorly defined. Here, it is shown that IL-36γ and IL-36Ra reciprocally regulate the progression of non-small cell lung cancer (NSCLC) by modulating glutathione metabolism and ROS resolution. Knockout, inhibition, or neutralization of IL-36γ significantly inhibits NSCLC progression and prolongs survival of the Kras Tp53 and Kras Lkb1 mice after tumor induction, whereas knockout of IL-36Ra exacerbates tumorigenesis in these NSCLC mouse models and accelerates death of mice. Mechanistically, IL-36γ directly upregulates an array of genes involved in glutathione homeostasis to reduce ROS and prevent oxidative stress-induced cell death, which is mitigated by IL-36Ra or IL-36γ neutralizing antibody. Consistently, IL-36γ staining is positively and negatively correlated with glutathione biosynthesis and ROS in human NSCLC tumor biopsies, respectively. These findings highlight essential roles of cytokine networks in redox for tumorigenesis and provide potential therapeutic strategy for NSCLC.
抗氧化剂和活性氧（ROS）之间的平衡对肿瘤的发生和发展起着至关重要的调节作用。然而，细胞因子网络是否以及如何控制有利于肿瘤的氧化还原状态仍未得到明确界定。本研究表明，IL-36γ 和 IL-36Ra 通过调节谷胱甘肽代谢和 ROS 清除来相互调节非小细胞肺癌（NSCLC）的进展。IL-36γ 的敲除、抑制或中和显著抑制 NSCLC 的进展，并延长 Kras Tp53 和 Kras Lkb1 小鼠在肿瘤诱导后的存活时间，而 IL-36Ra 的敲除则加剧了这些 NSCLC 小鼠模型中的肿瘤发生并加速了小鼠的死亡。在机制上，IL-36γ 直接上调一系列参与谷胱甘肽稳态的基因，以减少 ROS 并防止氧化应激诱导的细胞死亡，而 IL-36Ra 或 IL-36γ 中和抗体则减轻了这种作用。一致地，IL-36γ 染色与人类 NSCLC 肿瘤活检中的谷胱甘肽生物合成和 ROS 分别呈正相关和负相关。这些发现强调了细胞因子网络在氧化还原方面对肿瘤发生的重要作用，并为 NSCLC 提供了潜在的治疗策略。
