Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis
Mohammed L. Ibrahim,
John D. Klement,
Chunwan Lu,
Priscilla S. Redd,
Wei Xiao,
Dafeng Yang,
Darren D. Browning,
Natasha M. Savage,
Phillip J. Buckhaults,
Herbert C. Morse, III,
Kebin Liu
Affiliations
Mohammed L. Ibrahim
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
John D. Klement
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Chunwan Lu
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Priscilla S. Redd
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Wei Xiao
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Dafeng Yang
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Darren D. Browning
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Natasha M. Savage
Department of Pathology, Medical College of Georgia, Augusta, GA 30912, USA
Phillip J. Buckhaults
Department of Drug Discovery and Biomedical Sciences, the University of South Carolina, Columbia, SC 29208, USA
Herbert C. Morse, III
Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA
Kebin Liu
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA; Corresponding author
Summary: IL-10 functions as a suppressor of colitis and colitis-associated colon cancer, but it is also a risk locus associated with ulcerative colitis. The mechanism underlying the contrasting roles of IL-10 in inflammation and colon cancer is unknown. We report here that inflammation induces the accumulation of CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) that express high levels of IL-10 in colon tissue. IL-10 induces the 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 Irf8 deleted in colonic epithelial cells exhibit significantly higher inflammation-induced tumor incidence. Human colorectal carcinomas have significantly higher DNMT1 and DNMT3b and lower IRF8 expression, and they exhibit significantly higher IRF8 promoter DNA methylation than normal colon. Our data identify the MDSC-IL-10-STAT3-DNMT3b-IRF8 pathway as a link between chronic inflammation and colon cancer initiation. : Ibrahim et al. report that chronic inflammation induces colonic accumulation of myeloid-derived suppressor cells (MDSCs) that upregulates IL-10. IL-10 directly regulates STAT3 activation to upregulate DNMT3b to silence tumor suppressor IRF8 in colonic epithelial cells. The MDSC-IL-10-STAT3-DNMT3b-IRF8 pathway links chronic inflammation to colon cancer initiation. Keywords: colitis, MDSCs, IRF8, IL-10, STAT3, DNMT3b, colon cancer, chronic inflammation, colon tumorigenesis, DNA methylation
