T-bet knockout prevents Helicobacter felis-induced gastric cancer.
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.
Stoicov
Calin
C
Department of Medicine, University of Massachusetts Medical School, Worcester, 01635, USA.
Fan
Xueli
X
Liu
Jian Hua
JH
Bowen
Glennice
G
Whary
Mark
M
Kurt-Jones
Evelyn
E
Houghton
JeanMarie
J
D000230:Adenocarcinoma / Q000276:immunology / Q000382:microbiology* / Q000517:prevention & control*; D000818:Animals; D005260:Female; D005753:Gastric Mucosa / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D020022:Genetic Predisposition to Disease; D016481:Helicobacter Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D044922:Helicobacter felis / Q000276:immunology*; D053583:Interleukin-1beta / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013274:Stomach Neoplasms / Q000276:immunology / Q000382:microbiology* / Q000517:prevention & control*; D020825:T-Box Domain Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D000098815:T-bet Transcription Factor
D053583:Interleukin-1beta; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014409:Tumor Necrosis Factor-alpha