Abstract | BACKGROUND & AIMS: METHODS: We crossed Nfkb1-/- mice with Il6-/-, Il22-/-, Il11Rα-/-, and Tnf-/- mice. Stomach tissues from compound mutant mice were analyzed by histology, immunoblotting, and RNA sequencing. Lymphoid, myeloid, and epithelial cells were isolated from stomachs, and the levels of cytokines were determined by flow cytometric analysis. RESULTS: Nfkb1-/- mice developed gastritis, oxyntic atrophy, gastric dysplasia, and invasive tumors, whereas Nfkb1-/-Stat1-/- mice did not, even when followed for as long as 2 years. The levels of Il6, Il11, Il22, and Tnf messenger RNA were increased in the body and antrum of the stomachs from Nfkb1-/- mice, from 3-6 months of age. However, Nfkb1-/- Il6-/-, Nfkb1-/-Il22-/-, and Nfkb1-/-Il11Rα-/- mice still developed gastric tumors, although the absence of IL11 receptor (IL11R) significantly reduced development of invasive gastric tumors. Stomachs from Nfkb1-/-Tnf-/- mice exhibited significantly less gastritis and oxyntic atrophy and fewer tumors than Nfkb1-/- mice. This correlated with reduced activation of STAT1 and STAT3 and fewer numbers of T cells and B cells infiltrating the gastric body. Loss of STAT1 or TNF significantly reduced expression of PD-L1 on epithelial and myeloid (CD11b+) cells in the gastric mucosa of Nfkb1-/- mice-indeed, to the levels observed on the corresponding cells from wild-type mice. CONCLUSIONS: In studies of gastric tumor development in knockout mice, we found that loss of NFKB1 causes increased expression of TNF in the stomach and thereby drives activation of STAT1, resulting in an inflammatory immune response and the development of gastric cancer. IL11R appears to be required for the progression of gastric tumors to the invasive stage. These findings suggest that inhibitors of TNF, and possibly also inhibitors of IL11/IL11Rα, might be useful in the treatment of gastric cancer.
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Authors | Jun T Low, Michael Christie, Matthias Ernst, Laure Dumoutier, Adele Preaudet, Yanhong Ni, Michael D W Griffin, Lisa A Mielke, Andreas Strasser, Tracy L Putoczki, Lorraine A O'Reilly |
Journal | Gastroenterology
(Gastroenterology)
Vol. 159
Issue 4
Pg. 1444-1458.e15
(10 2020)
ISSN: 1528-0012 [Electronic] United States |
PMID | 32569771
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Interleukin-11
- Interleukin-6
- NF-kappa B p50 Subunit
- STAT1 Transcription Factor
- Tumor Necrosis Factor-alpha
- Nfkb1 protein, mouse
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Topics |
- Animals
- Carcinogenesis
- Gastritis
(etiology, metabolism, pathology)
- Interleukin-11
(metabolism)
- Interleukin-6
(metabolism)
- Mice
- NF-kappa B p50 Subunit
(metabolism)
- STAT1 Transcription Factor
(metabolism)
- Signal Transduction
- Stomach Neoplasms
(etiology, metabolism, pathology)
- Tumor Necrosis Factor-alpha
(metabolism)
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