Augusta University - Department of Biochemistry and Molecular Biology; Augusta University - Georgia Cancer Center; Government of the United States of America - Charlie Norwood VA Medical Center
Augusta University - Department of Biochemistry and Molecular Biology; Augusta University - Georgia Cancer Center; Government of the United States of America - Charlie Norwood VA Medical Center
Augusta University - Department of Biochemistry and Molecular Biology; Augusta University - Georgia Cancer Center; Government of the United States of America - Charlie Norwood VA Medical Center
Augusta University - Department of Biochemistry and Molecular Biology; Augusta University - Georgia Cancer Center; Government of the United States of America - Charlie Norwood VA Medical Center
IL10 is an anti-inflammatory cytokine that suppresses colitis and colitis-associated colon cancer, but it has recently been found to be a risk locus associated with ulcerative colitis. The mechanism underlying the contrasting roles of IL10 in inflammation and colon cancer is unknown. We report here that inflammation induces accumulation of CD11b+Gr1+ myeloid-derived suppressor cells that express high level of IL10 in colon tissue. IL10 induces activation of STAT3 that directly binds to the Dnmt1 and Dnmt3b promoters to activate their expression, resulting in DNA hypermethylation at the Irf8 promoter to silence IRF8 expression in colon epithelial cells. Mice with an Irf8 knock out in colonic epithelial cells exhibit a significantly higher inflammation-induced tumor incidence. Our data identify the MDSC-IL10-STAT3-DNMT-IRF8 pathway as a link between chronic inflammation and colon cancer initiation.
Ibrahim, Mohammed L. and Klement, John D. and Lu, Chunwan and Redd, Priscilla S. and Xiao, Wei and Yang, Dafeng and Morse, Herbert C. and Liu, Kebin, Myeloid-Derived Suppressor Cells Produce IL10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Tumorigenesis (2018). Available at SSRN: https://ssrn.com/abstract=3155812 or http://dx.doi.org/10.2139/ssrn.3155812
This version of the paper has not been formally peer reviewed.
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