El-Zaatari Mohamad, Bass Adam J, Bowlby Reanne, Zhang Min, Syu Li-Jyun, Yang Yitian, Grasberger Helmut, Shreiner Andrew, Tan Bei, Bishu Shrinivas, Leung Wai K, Todisco Andrea, Kamada Nobuhiko, Cascalho Marilia, Dlugosz Andrzej A, Kao John Y
Department of Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan.
Department of Medical Oncology and the Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts.
Gastroenterology. 2018 Jan;154(1):140-153.e17. doi: 10.1053/j.gastro.2017.09.002. Epub 2017 Sep 11.
BACKGROUND & AIMS: Chronic gastrointestinal inflammation increases the risk of cancer by mechanisms that are not well understood. Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-binding enzyme that regulates the immune response via catabolization and regulation of tryptophan availability for immune cell uptake. IDO1 expression is increased during the transition from chronic inflammation to gastric metaplasia. We investigated whether IDO1 contributes to the inflammatory response that mediates loss of parietal cells leading to metaplasia.
Chronic gastric inflammation was induced in Ido1 and CB57BL/6 (control) mice by gavage with Helicobacter felis or overexpression of interferon gamma in gastric parietal cells. We also performed studies in Jh mice, which are devoid of B cells. Gastric tissues were collected and analyzed by flow cytometry, immunostaining, and real-time quantitative polymerase chain reaction. Plasma samples were analyzed by enzyme-linked immunosorbent assay. Gastric tissues were obtained from 20 patients with gastric metaplasia and 20 patients without gastric metaplasia (controls) and analyzed by real-time quantitative polymerase chain reaction; gastric tissue arrays were analyzed by immunohistochemistry. We collected genetic information on gastric cancers from The Cancer Genome Atlas database.
H felis gavage induced significantly lower levels of pseudopyloric metaplasia in Ido1 mice, which had lower frequencies of gastric B cells, than in control mice. Blood plasma from H felis-infected control mice had increased levels of autoantibodies against parietal cells, compared to uninfected control mice, but this increase was lower in Ido1 mice. Chronically inflamed stomachs of Ido1 mice had significantly lower frequencies of natural killer cells in contact with parietal cells, compared with stomachs of control mice. Jh mice had lower levels of pseudopyloric metaplasia than control mice in response to H felis infection. Human gastric pre-neoplasia and carcinoma specimens had increased levels of IDO1 messenger RNA compared with control gastric tissues, and IDO1 protein colocalized with B cells. Co-clustering of IDO1 messenger RNA with B-cell markers was corroborated by The Cancer Genome Atlas database.
IDO1 mediates gastric metaplasia by regulating the B-cell compartment. This process appears to be associated with type II hypersensitivity/autoimmunity. The role of autoimmunity in the progression of pseudopyloric metaplasia warrants further investigation.
慢性胃肠道炎症通过尚不清楚的机制增加癌症风险。吲哚胺-2,3-双加氧酶1（IDO1）是一种血红素结合酶，通过分解代谢和调节色氨酸供免疫细胞摄取来调节免疫反应。在从慢性炎症向胃化生转变过程中，IDO1表达增加。我们研究了IDO1是否促成介导壁细胞丢失导致化生的炎症反应。
通过向Ido1和CB57BL/6（对照）小鼠胃内灌喂猫幽门螺杆菌或在胃壁细胞中过表达γ干扰素诱导慢性胃炎症。我们还在缺乏B细胞的Jh小鼠中进行了研究。收集胃组织，通过流式细胞术、免疫染色和实时定量聚合酶链反应进行分析。通过酶联免疫吸附测定分析血浆样本。从20例胃化生患者和20例无胃化生患者（对照）获取胃组织，通过实时定量聚合酶链反应进行分析；通过免疫组织化学分析胃组织芯片。我们从癌症基因组图谱数据库收集胃癌的遗传信息。
与对照小鼠相比，灌喂猫幽门螺杆菌后，胃B细胞频率较低的Ido1小鼠假幽门化生水平显著降低。与未感染的对照小鼠相比，感染猫幽门螺杆菌的对照小鼠血浆中抗壁细胞自身抗体水平升高，但在Ido1小鼠中这种升高较低。与对照小鼠的胃相比，Ido1小鼠慢性炎症胃中与壁细胞接触的自然杀伤细胞频率显著降低。对猫幽门螺杆菌感染的反应中，Jh小鼠的假幽门化生水平低于对照小鼠。与对照胃组织相比，人胃肿瘤前病变和癌标本中IDO1信使核糖核酸水平升高，且IDO1蛋白与B细胞共定位。癌症基因组图谱数据库证实了IDO1信使核糖核酸与B细胞标志物的共聚类。
IDO1通过调节B细胞区室介导胃化生。这一过程似乎与II型超敏反应/自身免疫相关。自身免疫在假幽门化生进展中的作用值得进一步研究。
