RESUMEN
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 IL1ß 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, IL1ß or IFN-γ with or without kif3a siRNA. RESULTS: IFN-γ increased gastrin and induced antral hyperplasia. However, antral expression of IL1ß 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, IL1ß treatment doubled primary cilia length, induced GLI2 and suppressed gastrin gene expression. Knocking down kif3a in GLUTAg cells mitigated SHH or IL1ß suppression of gastrin. CONCLUSIONS: Overexpression of IL1ß in the antrum was sufficient to induce antral hyperplasia coincident with suppression of gastrin via primary cilia. ORCID: #0000-0002-6559-8184.