Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis

Cell Rep. 2018 Dec 11;25(11):3036-3046.e6. doi: 10.1016/j.celrep.2018.11.050.


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.

Keywords: DNA methylation; DNMT3b; IL-10; IRF8; MDSCs; STAT3; chronic inflammation; colitis; colon cancer; colon tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinogenesis / metabolism*
  • Colitis / complications*
  • Colonic Neoplasms / etiology*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Methylation / genetics
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Inflammation / pathology
  • Interferon Regulatory Factors / genetics*
  • Interferon Regulatory Factors / metabolism
  • Interleukin-10 / biosynthesis*
  • Mice, Inbred C57BL
  • Myeloid-Derived Suppressor Cells / metabolism*
  • Promoter Regions, Genetic
  • STAT3 Transcription Factor / metabolism
  • Up-Regulation


  • Interferon Regulatory Factors
  • STAT3 Transcription Factor
  • interferon regulatory factor-8
  • Interleukin-10
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3B