T-bet knockout prevents Helicobacter felis-induced gastric cancer
Graduate School of Biomedical Sciences, MD/PhD Program; Department of Medicine, Division of Gastroenterology; Department of Cancer Biology
Medical Subject Headings
Adenocarcinoma; Animals; Female; Gastric Mucosa; Genetic Predisposition to Disease; Helicobacter Infections; Helicobacter felis; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Stomach Neoplasms; T-Box Domain Proteins; Tumor Necrosis Factor-alpha
Helicobacter infection is the primary risk factor for gastric cancer, with the cytokine environment within the gastric mucosa the strongest predictor of disease risk. Elevated TNF-alpha, IL-1beta, and low IL-10 are associated with the highest risk. In this study, we used C57BL/6 mice to identify T-bet as a central regulator of the cytokine environment during Helicobacter felis infection. We infected male and female C57BL/6 and C57BL/6-T-bet knockout (KO) litter mates with H. felis and examined the bacterial colonization, immune response, and mucosal damage at varying time points. T-bet KO mice maintained infection for 15 mo at similar levels to wild-type mice. Infection and immune response did not differ between male and female mice. Despite sustained infection, T-bet KO mice respond with a blunted Th1 response associated with preservation of parietal and chief cells and protection from the development of gastric cancer. Unexpectedly, T-bet KO mice develop a gastric environment that would not be expected based on the phenotype of T-bet KO CD4 cells alone. T-bet KO mice respond to H. felis infection with a markedly blunted IL-1beta and TNF-alpha and elevated IL-10 levels. Activity of this one master regulator modulates the expression of the key gastric mucosal cytokines associated with gastric cancer and may be a target for therapy to restore immune balance clinically in patients at risk for gastric cancer.
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Citation: J Immunol. 2009 Jul 1;183(1):642-9. Epub 2009 Jun 17.