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Cell Mol Gastroenterol Hepatol. 2018 Jan 2;5(4):678-690.e1. doi: 10.1016/j.jcmgh.2017.12.012. eCollection 2018.

Interleukin-17A Promotes Parietal Cell Atrophy by Inducing Apoptosis.

Author information

1
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St Louis, Missouri.
2
Division of Gastroenterology, Departments of Medicine, Pathology and Immunology, Developmental Biology, Washington University School of Medicine, St Louis, Missouri.
3
Nashville VA Medical Center and Departments of Surgery and Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.

Abstract

Background & Aims:

Atrophic gastritis caused by chronic inflammation in the gastric mucosa leads to the loss of gastric glandular cells, including acid-secreting parietal cells. Parietal cell atrophy in a setting of chronic inflammation induces spasmolytic polypeptide expressing metaplasia, a critical step in gastric carcinogenesis. However, the mechanisms by which inflammation causes parietal cell atrophy and spasmolytic polypeptide expressing metaplasia are not well defined. We investigated the role of interleukin-17A (IL-17A) in causing parietal cell atrophy.

Methods:

A mouse model of autoimmune atrophic gastritis was used to examine IL-17A production during early and late stages of disease. Organoids derived from corpus glands were used to determine the direct effects of IL-17A on gastric epithelial cells. Immunofluorescent staining was used to examine IL-17A receptors and the direct effect of signaling on parietal cells. Mice were infected with an IL-17A-producing adenovirus to determine the effects of IL-17A on parietal cells in vivo. Finally, IL-17A neutralizing antibodies were administered to mice with active atrophic gastritis to evaluate the effects on parietal cell atrophy and metaplasia.

Results:

Increased IL-17A correlated with disease severity in mice with chronic atrophic gastritis. IL-17A caused caspase-dependent gastric organoid degeneration, which could not be rescued with a necroptosis inhibitor. Parietal cells expressed IL-17A receptors and IL-17A treatment induced apoptosis in parietal cells. Overexpressing IL-17A in vivo induced caspase-3 activation and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining in parietal cells. Finally, IL-17A neutralizing antibody decreased parietal cell atrophy and metaplasia in mice with chronic atrophic gastritis.

Conclusions:

These data identify IL-17A as a cytokine that promotes parietal cell apoptosis during atrophic gastritis, a precursor lesion for gastric cancer.

KEYWORDS:

ADV, adenovirus; Apoptosis; Atrophy; IL-17A; IL-17A, interleukin 17A; Metaplasia; SPEM, spasmolytic polypeptide-expressing metaplasia; TUNEL, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling; Th, T helper; rIL-17A, recombinant interleukin 17A

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