Open AccessLoss of adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22
Author(s) -
Yu Chen,
Maud Vandereyken,
Ian P. Newton,
Ignacio Moraga,
Inke Näthke,
Mahima Swamy
Publication year - 2019
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3000540
Subject(s) - biology , adenomatous polyposis coli , carcinogenesis , stat3 , cancer research , histone , stat protein , cytokine , familial adenomatous polyposis , microbiology and biotechnology , signal transduction , immunology , genetics , gene , colorectal cancer , cancer
Interleukin-22 (IL-22) is a critical immune defence cytokine that maintains intestinal homeostasis and promotes wound healing and tissue regeneration, which can support the growth of colorectal tumours. Mutations in the adenomatous polyposis coli gene ( Apc ) are a major driver of familial colorectal cancers (CRCs). How IL-22 contributes to APC-mediated tumorigenesis is poorly understood. To investigate IL-22 signalling in wild-type (WT) and APC-mutant cells, we performed RNA sequencing (RNAseq) of IL-22–treated murine small intestinal epithelial organoids. In WT epithelia, antimicrobial defence and cellular stress response pathways were most strongly induced by IL-22. Surprisingly, although IL-22 activates signal transducer and activator of transcription 3 (STAT3) in APC-mutant cells, STAT3 target genes were not induced. Our analyses revealed that Apc Min/Min cells are resistant to IL-22 due to reduced expression of the IL-22 receptor, and increased expression of inhibitors of STAT3, particularly histone deacetylases (HDACs). We further show that IL-22 increases DNA damage and genomic instability, which can accelerate cellular transition from heterozygosity ( Apc Min/+ ) to homozygosity (Apc Min/Min ) to drive tumour formation. Our data reveal an unexpected role for IL-22 in promoting early tumorigenesis while excluding a function for IL-22 in transformed epithelial cells.