P-295 IL-33 Drives Pre-cancerous Events Mediated by Epithelial Metaplasia in the Stomach

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Abstract

Background:

IL-33 is a new member of the IL-1 cytokine family known to promote, epithelial hyperplasia, most prominently for goblet cells, within the GI and airway mucosa and has been linked to several autoimmune and inflammatory disorders, including inflammatory bowel disease (IBD). Emerging evidence suggests that IL-33 is important in the development of GI-related cancers, including gastric cancer. We characterized the features and mechanisms of chronic gastritis in SAMP1/YitFc (SAMP) mice, a spontaneous model of Crohn's Disease-like ileitis, in which gastritis develops spontaneously and IL-33 is up-regulated. Loss of parietal cells in the stomach causes the development of spasmolytic polypeptide-expressing metaplasia (SPEM) through transdifferentiation of chief cells. In the presence of inflammation, SPEM can advance into a more proliferative metaplasia with increased expression of intestine-specific transcripts. In this context, IL-33 represents an ideal candidate cytokine that may be critical in promoting the gastritis-metaplasia-carcinoma sequence due to its ability to potently stimulate epithelial proliferation and metaplasia.

Methods:

Four and-20-week-old SAMP and age-matched AKR/J (AKR) parental strain control were used to evaluate baseline SPEM and progression to intestinalized SPEM. For IL-33 administration experiments, 8-week-old AKR were injected i.p. (33 μg/kg, daily for 1 wk) with either murine rIL-33 or PBS (vehicle controls) and then euthanized for tissue collection.

Results:

In SAMP Alcian Blue/PAS staining showed an increased intense blue staining along the body and at the base of corpus glands, indicating the presence of acid mucins which are commonly found in gastric metaplasia and gastric adenocarcinoma. Furthermore, evaluation of full-thickness corpus tissues for expression of markers of normal gastric homeostasis, Gif, Atp4a, and Tff1, showed a striking decrease in 20-week-old SAMP versus age-matched AKR. Moreover, SPEM (He4 and Clu), as well as intestinalized SPEM (Dmbt1 and Cftr) markers were dramatically increased in 20-week-old SAMP versus age-matched AKR. After IL-33 administration to AKR mice the stomach developed thickened gastric mucosal folds, which were absent in vehicle-treated mice. Histologic evaluation of these folds revealed overall hypertrophy of the gastric mucosa, epithelial hyperplasia, as well as oxyntic and chief cell atrophy. Vehicle-treated AKR instead showed healthy stomach morphology, with normal presence and localization of parietal and chief cells. The emergence of prominent hyperplastic mucus neck cells was detected in IL-33-treated AKR and appeared deep blue upon alcian blue/PAS staining, but were absent in vehicle-treated mice. Consistent with parietal cell loss, expression of Gif and Atp4a was potently downregulated in whole corpus tissues from IL-33-treated AKR, and Tff1 showed a similar trend towards decreased expression. He4 and Clu were consistently upregulated after IL-33, however, only Cftr was considerably increased for the intestinalized SPEM markers assayed. The presence of SPEM in IL-33-treated AKR was further characterized by prominent proliferation of cells within the gastric glands, demonstrated by a greater number of BrdU+ cells present along the neck and at the base of the glands, and by increased epithelial hyperplasia.

Conclusions:

Taken together, our data suggest that IL-33 may play an important role in the early events leading to intestinalized gastric metaplasia by promoting epithelial proliferation in the stomach of gastritis-prone SAMP mice.

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