Interleukin-1β Suppresses Gastrin via Primary Cilia and Induces Antral Hyperplasia

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 IL1 beta or IFN-gamma 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, IL1 beta or IFN-gamma with or without kif3a siRNA. RESULTS: IFN-gamma increased gastrin and induced antral hyperplasia. However, antral expression of IL1 beta suppressed tissue and serum gastrin, while also inducing antral hyperplasia. IFN-gamma treatment of GLUTAg cells suppressed GLI2 and induced gastrin, without affecting cilia length. By contrast, IL1 beta treatment doubled primary cilia length, induced GLI2 and suppressed gastrin gene expression. Knocking down kif3a in GLUTAg cells mitigated SHH or IL1 beta suppression of gastrin. CONCLUSIONS: Overexpression of IL1 beta in the antrum was sufficient to induce antral hyperplasia coincident with suppression of gastrin via primary cilia.

Automated summary

In the study, it was found that IL1 beta and IFN-gamma have different effects in the gastric antrum, with IL1 beta inducing antral hyperplasia and suppressing gastrin expression, while IFN-gamma increases gastrin and induces antral hyperplasia.