Bockerstett Kevin A, Osaki Luciana H, Petersen Christine P, Cai Catherine W, Wong Chun Fung, Nguyen Thanh-Long M, Ford Eric L, Hoft Daniel F, Mills Jason C, Goldenring James R, DiPaolo Richard J
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St Louis, Missouri.
Division of Gastroenterology, Departments of Medicine, Pathology and Immunology, Developmental Biology, Washington University School of Medicine, St Louis, Missouri.
Cell Mol Gastroenterol Hepatol. 2018 Jan 2;5(4):678-690.e1. doi: 10.1016/j.jcmgh.2017.12.012. eCollection 2018.
BACKGROUND & AIMS: Atrophic gastritis caused by chronic inflammation in the gastric mucosa leads to the loss of gastric glandular cells, including acid-secreting parietal cells. Parietal cell atrophy in a setting of chronic inflammation induces spasmolytic polypeptide expressing metaplasia, a critical step in gastric carcinogenesis. However, the mechanisms by which inflammation causes parietal cell atrophy and spasmolytic polypeptide expressing metaplasia are not well defined. We investigated the role of interleukin-17A (IL-17A) in causing parietal cell atrophy.
A mouse model of autoimmune atrophic gastritis was used to examine IL-17A production during early and late stages of disease. Organoids derived from corpus glands were used to determine the direct effects of IL-17A on gastric epithelial cells. Immunofluorescent staining was used to examine IL-17A receptors and the direct effect of signaling on parietal cells. Mice were infected with an IL-17A-producing adenovirus to determine the effects of IL-17A on parietal cells in vivo. Finally, IL-17A neutralizing antibodies were administered to mice with active atrophic gastritis to evaluate the effects on parietal cell atrophy and metaplasia.
Increased IL-17A correlated with disease severity in mice with chronic atrophic gastritis. IL-17A caused caspase-dependent gastric organoid degeneration, which could not be rescued with a necroptosis inhibitor. Parietal cells expressed IL-17A receptors and IL-17A treatment induced apoptosis in parietal cells. Overexpressing IL-17A in vivo induced caspase-3 activation and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in parietal cells. Finally, IL-17A neutralizing antibody decreased parietal cell atrophy and metaplasia in mice with chronic atrophic gastritis.
These data identify IL-17A as a cytokine that promotes parietal cell apoptosis during atrophic gastritis, a precursor lesion for gastric cancer.
胃黏膜慢性炎症所致的萎缩性胃炎会导致胃腺细胞丢失，包括分泌胃酸的壁细胞。慢性炎症背景下的壁细胞萎缩会诱发表达解痉多肽的化生，这是胃癌发生过程中的关键步骤。然而，炎症导致壁细胞萎缩和表达解痉多肽化生的机制尚不清楚。我们研究了白细胞介素-17A（IL-17A）在导致壁细胞萎缩中的作用。
采用自身免疫性萎缩性胃炎小鼠模型，检测疾病早期和晚期IL-17A的产生情况。利用胃体腺来源的类器官，确定IL-17A对胃上皮细胞的直接作用。采用免疫荧光染色检测IL-17A受体以及信号传导对壁细胞的直接作用。用产生IL-17A的腺病毒感染小鼠，以确定IL-17A对体内壁细胞的影响。最后，给患有活动性萎缩性胃炎的小鼠注射IL-17A中和抗体，以评估其对壁细胞萎缩和化生的影响。
慢性萎缩性胃炎小鼠中，IL-17A水平升高与疾病严重程度相关。IL-17A导致半胱天冬酶依赖性胃类器官退化，坏死性凋亡抑制剂无法挽救这种退化。壁细胞表达IL-17A受体，IL-17A处理可诱导壁细胞凋亡。体内过表达IL-17A可诱导壁细胞中半胱天冬酶-3激活和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记染色。最后，IL-17A中和抗体可减轻慢性萎缩性胃炎小鼠的壁细胞萎缩和化生。
这些数据表明，IL-17A是一种在萎缩性胃炎（胃癌的前驱病变）期间促进壁细胞凋亡的细胞因子。
