Background & Aims

Helicobacter pylori infection in humans typically begins with colonization of the gastric antrum. The initial Th1 response occasionally coincides with an increase in gastrin secretion. Subsequently, the gastritis segues to chronic atrophic gastritis, metaplasia, dysplasia and distal gastric cancer. Despite these well characterized clinical events, the link between inflammatory cytokines and non-cardia gastric cancer remains difficult to study in mouse models. Prior studies have demonstrated that overexpression of the Hedgehog (HH) effector GLI2 induces loss of gastrin (atrophy) and antral hyperplasia. To determine the link between specific cytokines, HH signaling and pre-neoplastic changes in the gastric antrum.

Methods

Mouse lines were created to conditionally direct IL1β or IFN-γ to the antrum using the Gastrin-CreERT2 and Tet activator. Primary cilia, which transduces HH signaling, on G cells were disrupted by deleting the ciliary motor protein KIF3a. Phenotypic changes were assessed by histology and western blots. A subclone of GLUTag enteroendocrine cells selected for gastrin expression and the presence of primary cilia was treated with recombinant SHH, IL1β or IFN-γ with or without kif3a siRNA.

Results

IFN-γ increased gastrin and induced antral hyperplasia. However, antral expression of IL1β suppressed tissue and serum gastrin, while also inducing antral hyperplasia. IFN-γ treatment of GLUTAg cells suppressed GLI2 and induced gastrin, without affecting cilia length. By contrast, IL1β treatment doubled primary cilia length, induced GLI2 and suppressed gastrin gene expression. Knocking down kif3a in GLUTAg cells mitigated SHH or IL1β suppression of gastrin.

Conclusions

Overexpression of IL1β in the antrum was sufficient to induce antral hyperplasia coincident with suppression of gastrin via primary cilia. ORCID: #0000-0002-6559-8184

中文翻译：

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白细胞介素 1β 通过原发性纤毛抑制胃泌素并诱导胃窦增生

背景与目标

人类的幽门螺杆菌感染通常始于胃窦的定植。最初的 Th1 反应偶尔会与胃泌素分泌的增加同时发生。随后，胃炎发展为慢性萎缩性胃炎、化生、异型增生和远端胃癌。尽管有这些特征明确的临床事件，但炎性细胞因子与非贲门胃癌之间的联系仍然难以在小鼠模型中研究。先前的研究表明，Hedgehog (HH) 效应子 GLI2 的过表达会导致胃泌素丧失（萎缩）和胃窦增生。确定特定细胞因子、HH 信号传导和胃窦癌前变化之间的联系。

方法

使用Gastrin-CreERT2和 Tet 激活剂创建小鼠系以有条件地将 IL1β 或 IFN-γ 引导至胃窦。通过删除纤毛运动蛋白 KIF3a 破坏了 G 细胞上转导 HH 信号传导的初级纤毛。通过组织学和蛋白质印迹评估表型变化。选择用于胃泌素表达和初级纤毛存在的 GLUTag 肠内分泌细胞亚克隆用重组 SHH、IL1β 或 IFN-γ 处理，有或没有kif3a siRNA。

结果

IFN-γ增加胃泌素并诱导胃窦增生。然而，IL1β 的胃窦表达抑制了组织和血清胃泌素，同时也诱导了胃窦增生。GLUTAg 细胞的 IFN-γ 处理抑制 GLI2 并诱导胃泌素，而不影响纤毛长度。相比之下，IL1β 处理使原发性纤毛长度加倍，诱导 GLI2 并抑制胃泌素基因表达。敲除 GLUTAg细胞中的 kif3a 可减轻 SHH 或 IL1β 对胃泌素的抑制。

结论

胃窦中 IL1β 的过表达足以诱导胃窦增生，同时通过初级纤毛抑制胃泌素。兽人：#0000-0002-6559-8184