The Role of Epstein-Barr Virus-Induced Gene 3 (EBI3) in Preventing Gastric Atrophy and Metaplasia

项目总结 胃萎缩和化生是促进胃癌发生的关键上皮细胞变化。 胃癌是世界范围内的一个重大公共卫生问题，是癌症相关死亡的第三大原因。 在世界上每年有近100万名受害者。慢性炎症是一个主要的易感危险因素。 对于胃癌的发展，以慢性萎缩性胃炎患者为例 比健康的同龄人患癌症的风险要高得多。而慢性疾病之间的联系 炎症和癌症的风险是明确的，胃部炎症过程的确切机制 在一些患者中会导致癌症发生，但其他患者并不是不了解。有一个复杂的细胞因子环境 与任何慢性炎症过程和细胞因子基因多态性有关的人类患者 已被证明对患胃癌的风险有显著影响。归因于强者 炎症过程中细胞因子的长时间产生与胃癌风险增加之间的关系 我们感兴趣的是确定细胞因子在调节肿瘤发展中所起的机械作用。 慢性胃炎时的胃萎缩和化生。 EB病毒诱导基因3(EBI3)编码细胞因子IL-27的一个蛋白亚基(EBI3)。 描述并记录了炎症过程中对CD4T细胞的影响。EBI3也是 鲜为人知的免疫抑制细胞因子IL-35被认为是由调节性T细胞(Treg)产生的。我们 使用一种新的炎症诱导的胃萎缩和化生的小鼠模型TxA23。在此模型中，我们 发现Ebi3产生不足的小鼠加速了萎缩和 痉挛多肽表达化生(SPEM)，重要的癌前上皮细胞病变。我们 也观察到tregs，它是胃炎和由此引起的病变的关键抑制因子，表现出 Ebi3-/-小鼠的缺陷表型。然而，目前尚不清楚这种缺陷是否由于外在的IL-2缺乏所致。 27信号或天生不能表达Ebi3，从而表达IL-35。 我们的假设是，EBI3的表达在抑制胃炎、胃萎缩、 而胃化生部分是由于IL-27作用于Treg并增强其抑制作用所致 功能。在目标1中，我们将确定IL-27是否是关键的EBI3，包含负责 抑制疾病的发展。在目标2中，我们将确定IL-27信号在Tregs中的作用 胃萎缩和化生的发展。

PROJECT SUMMARY Gastric atrophy and metaplasia are critical epithelial cell changes that promote gastric carcinogenesis. Gastric cancer is a major public health issue world-wide, being the third leading cause of cancer-related death in the world with nearly one million victims every year. Chronic inflammation is a major predisposing risk factor for the development of gastric cancer, demonstrated by the fact that patients with chronic atrophic gastritis have significantly higher risk of cancer than their healthy peers. While the association between chronic inflammation and cancer risk is clear, the exact mechanisms by which the inflammatory process in the stomach leads to carcinogenesis in some patients but not others are not understood. There is a complex cytokine milieu associated with any chronic inflammatory process, and polymorphisms in cytokine genes in human patients have been shown to have a significant effect on the risk of gastric cancer development. Due to the strong association between the prolonged cytokine production during inflammation and increased gastric cancer risk, we are interested in determining the mechanistic role that cytokines serve in regulating the development of gastric atrophy and metaplasia during chronic gastritis. Epstein-Barr Virus-Induced Gene 3 (Ebi3) encodes a protein subunit (EBI3) of the cytokine IL-27, which is well- characterized and has documented effects on CD4+ T cells during inflammation. EBI3 is also a component of the poorly understood immunosuppressive cytokine IL-35 thought to be made by regulatory T cells (Tregs). We use a novel murine model of inflammation-induced gastric atrophy and metaplasia, TxA23. In this model we have discovered that mice deficient in the production of Ebi3 have accelerated development of atrophy and spasmolytic polypeptide expressing metaplasia (SPEM), important preneoplastic epithelial cell lesions. We have also observed that Tregs, which are critical suppressors of gastritis and resulting lesions, exhibit a defective phenotype in Ebi3-/- mice. However, it is unclear whether this defect is due to the extrinsic lack of IL- 27 signaling or the intrinsic inability to express Ebi3, and thereby IL-35. Our hypothesis is that EBI3 expression is critical for suppressing the development of gastritis, gastric atrophy, and gastric metaplasia due in part to the effects of IL-27 acting on Tregs and increasing their suppressive functions. In Aim 1 we will determine whether IL-27 is the critical EBI3 containing cytokine responsible for suppressing disease progression. In Aim 2, we will determine the effect of IL-27 signaling into Tregs during the development of gastric atrophy and metaplasia.