Loss of Tff1 promotes pro-inflammatory phenotype with increase in the levels of RORγt+ T lymphocytes and Il-17 in mouse gastric neoplasia

Mohammed Soutto, Mohamed Saleh, Mohamed S. Arredouani, Blanca Piazuelo, Abbes Belkhiri, Wael El-Rifai

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Background: TFF1 deficiency induces a mucosal pro-inflammatory phenotype that contributes to gastric tumorigenesis in mouse and human. Methods: We utilized the Tff1-KO mouse model to assess the impact of TFF1 loss on immune cells infiltration in the stomach. We used single cell suspension, flow cytometry, immunohistochemistry, and quantitative PCR (qPCR) assays. Results: The Tff1-KO gastric mucosa demonstrated high chronic inflammatory scores (score: 3-4) at age 2 months, which exacerbated at age 8 months (score: 4-6). We next used single-cell suspensions for flow cytometry analysis of total leukocytes (CD45+ cells), total T lymphocytes (CD45+CD3+cells), T cell subsets (CD4+, CD8+, and CD3+CD4-CD8-cells), and monocytes/macrophages (CD45+F4/80+cells). The results demonstrated an age-dependent (2 → 8 month age) significant increase of leukocytes (p < 0.05), T cells (p < 0.05), and monocytes/macrophages (p < 0.001) in the gastric mucosa of the Tff1-KO mice, as compared to Tff1-WT. A similar increase was observed in blood samples (p < 0.05). Using ionomycin to activate CD4+ splenocytes, the results indicated that Tff1-KO CD4+ splenocytes secreted higher levels of IL-17A (p < 0.05 at 2 and p < 0.001 at 8 months) and IL-17F (p < 0.05 at 2 and 8 months) than Tff1-WT splenocytes. Conversely, Tff1-KO CD8+-cells secreted less IL-17F, but comparable levels of IL-17A. In addition, we detected a significant upregulation of Il-17 mRNA expression in gastric tissues in the Tff1-KO, as compared to Tff1-WT (p < 0.001). Conclusions: The results identify TFF1 loss as a major pro-inflammatory step that modulates the tumor microenvironment and immune cell infiltration in the stomach. Furthermore, the data suggest that the increase of IL-17A and IL-17F in TH17 cells, derived from CD4+ T cells, reflects the chronic inflammation in gastric mucosa, whereas the absence of change of IL-17A and decrease of IL-17F in CD8+Tc17 cells suggest loss of cytotoxic function of CD8+Tc17 cells during gastric tumorigenesis of the Tff1-KO mice.

Original languageEnglish (US)
Pages (from-to)2424-2435
Number of pages12
JournalJournal of Cancer
Volume8
Issue number13
DOIs
StatePublished - 2017

Keywords

  • CD8
  • Gastric cancer
  • Il-17
  • Immune cells
  • Lymphocytes
  • TFF1

ASJC Scopus subject areas

  • Oncology

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