Work

Loss of Tff1 Promotes Pro-Inflammatory Phenotype with Increase in the Levels of RORγt+ T Lymphocytes and Il-17 in Mouse Gastric Neoplasia

Year: 2017

Type: article

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.

Source: Journal of Cancer

DOI: 10.7150/jca.19639

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