Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Dr Molewaterplein 40, Rotterdam, GD 3015, the Netherlands.
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Dr Molewaterplein 40, Rotterdam, GD 3015, the Netherlands; Department of Infectious Diseases, Leiden University Medical Centre, the Netherlands; Department of Parasitology, Leiden University Medical Centre, the Netherlands.
Neoplasia. 2024 Apr;50:100981. doi: 10.1016/j.neo.2024.100981. Epub 2024 Feb 28.
Helicobacter pylori (H. pylori) is a significant risk factor for development of gastric cancer (GC), one of the deadliest malignancies in the world. However, the mechanism by which H. pylori induces gastric oncogenesis remains unclear. Here, we investigated the function of IL-6 in gastric oncogenesis and macrophage-epithelial cell interactions.
We analyzed publicly available datasets to investigate the expression of IL-6 and infiltration of M2 macrophages in GC tissues, and determine the inter-cellular communication in the context of IL-6. Human gastric epithelial and macrophage cell lines (GES-1 and THP-1-derived macrophages, respectively) were used in mono- and co-culture experiments to investigate autocrine-and paracrine induction of IL-6 expression in response to H. pylori or IL-6 stimulation.
We found that IL-6 is highly expressed in GC and modulates survival. M2 macrophage infiltration is predominant in GC and drives an IL-6 mediated communication with gastric epithelium cells. In vitro, IL-6 triggers its own expression in GES-1 and THP-1-derived macrophages cells. In addition, these cell lines are able to upregulate each other's IL-6 levels in an autocrine fashion, which is enhanced by H. pylori stimulation.
This study indicates that IL-6 in the tumor microenvironment is essential for intercellular communication. We show that H. pylori enhances an IL-6-driven autocrine and paracrine positive feedback loop between macrophages and gastric epithelial cells, which may contribute to gastric carcinogenesis.
幽门螺杆菌（H. pylori）是胃癌（GC）发展的重要危险因素，胃癌是世界上最致命的恶性肿瘤之一。然而，H. pylori 诱导胃癌发生的机制尚不清楚。在这里，我们研究了白细胞介素 6（IL-6）在胃癌发生和巨噬细胞-上皮细胞相互作用中的功能。
我们分析了公开可用的数据集，以研究 IL-6 的表达和 GC 组织中 M2 巨噬细胞的浸润，并确定了在 IL-6 背景下细胞间的通讯。我们使用人胃上皮细胞系（GES-1）和巨噬细胞系（THP-1 衍生的巨噬细胞）进行单核和共培养实验，以研究 H. pylori 或 IL-6 刺激对 IL-6 表达的自分泌和旁分泌诱导。
我们发现 IL-6 在 GC 中高度表达并调节细胞存活。M2 巨噬细胞浸润在 GC 中占主导地位，并与胃上皮细胞发生 IL-6 介导的通讯。在体外，IL-6 触发 GES-1 和 THP-1 衍生的巨噬细胞中自身的表达。此外，这些细胞系能够以自分泌的方式上调彼此的 IL-6 水平，这种上调被 H. pylori 刺激增强。
本研究表明肿瘤微环境中的 IL-6 对于细胞间通讯至关重要。我们表明，H. pylori 增强了巨噬细胞和胃上皮细胞之间的 IL-6 驱动的自分泌和旁分泌正反馈回路，这可能有助于胃癌的发生。
