Abstract
Interleukin 22 (IL-22) is critical in maintaining homeostasis in the intestine by regulating the balance between pathogenic and commensal bacteria. IL-22 also promotes wound healing and tissue regeneration, which can support the growth of colorectal tumours. Mutations in the tumour suppressor Adenomatous Polyposis Coli gene (Apc) cause intestinal tumorigenesis and are a major driver of familial colorectal cancers. To understand the role of IL-22 in APC-mediated tumorigenesis, we analysed IL-22 signalling in wild-type (WT) and APC-mutant cells in small intestinal epithelial organoids and in mice. In WT epithelia, antimicrobial defence, mucus production, and cellular stress response pathways were most strongly upregulated by IL-22. Surprisingly, we found that although IL-22 activates STAT3 in APC-mutant cells, STAT3 target genes were not effectively induced. Our analyses revealed that ApcMin/Min cells are resistant to IL-22 due to reduced expression of the IL-22 receptor, and increased expression of inhibitors of STAT3, including histone deacetylases. We further show that IL-22 induced expression of nitric oxide synthase in WT epithelial cells, leading to DNA damage. These findings suggest that IL-22 does not promotes tumour formation by driving the proliferation of transformed intestinal epithelial cells. Rather, IL-22 increases genetic instability, which could accelerate transition from heterozygous ApcMin/+ to homozygous ApcMin/Min genotype that eventually drives tumour progression.
