@article{1c5f960511994b9685121b3cec25c989,
title = "Interleukin-17A Promotes Parietal Cell Atrophy by Inducing Apoptosis",
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 = "Apoptosis, Atrophy, IL-17A, Metaplasia",
author = "Bockerstett, {Kevin A.} and Osaki, {Luciana H.} and Petersen, {Christine P.} and Cai, {Catherine W.} and Wong, {Chun Fung} and Nguyen, {Thanh Long M.} and Ford, {Eric L.} and Hoft, {Daniel F.} and Mills, {Jason C.} and Goldenring, {James R.} and DiPaolo, {Richard J.}",
note = "Funding Information: Funding Supported by the American Cancer Society ( RSG-12-171-01-LIB ) and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases ( RO1 DK110406 ) (R.J.D. and J.C.M.); a grant from the Digestive Diseases Research Core Center of the Washington University School of Medicine (National Institute of Diabetes and Digestive and Kidney Diseases grant P30DK52574) and by the American Gastroenterological Association Funderburg Research Award (R.J.D.); a VA Merit Review (1I01BX000930) and National Institutes of Health grant DK101332 (J.R.G.); a National Institutes of Health National Research Service Award Predoctoral Fellowship ( F31 DK104600 to C.P.P.); and a pre-Program Projects Grants award from the Siteman Cancer Center and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases ( R01 DK094989 and R01 DK105129 to J.C.M.). Funding Information: Funding Supported by the American Cancer Society (RSG-12-171-01-LIB) and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (RO1 DK110406) (R.J.D. and J.C.M.); a grant from the Digestive Diseases Research Core Center of the Washington University School of Medicine (National Institute of Diabetes and Digestive and Kidney Diseases grant P30DK52574) and by the American Gastroenterological Association Funderburg Research Award (R.J.D.); a VA Merit Review (1I01BX000930) and National Institutes of Health grant DK101332 (J.R.G.); a National Institutes of Health National Research Service Award Predoctoral Fellowship (F31 DK104600 to C.P.P.); and a pre-Program Projects Grants award from the Siteman Cancer Center and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK094989 and R01 DK105129 to J.C.M.). Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
doi = "10.1016/j.jcmgh.2017.12.012",
language = "English",
volume = "5",
pages = "678--690.e1",
journal = "CMGH",
issn = "2352-345X",
number = "4",
}