Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis

WJ Chae, TF Gibson, D Zelterman… - Proceedings of the …, 2010 - National Acad Sciences
WJ Chae, TF Gibson, D Zelterman, L Hao, O Henegariu, ALM Bothwell
Proceedings of the National Academy of Sciences, 2010National Acad Sciences
The intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not
been addressed previously to our knowledge. Ablation of IL-17A significantly reduced tumor
development in mice bearing a heterozygote mutation in the adenomatous polyposis coli
(APC) gene (ApcMin/+ mice). There was also a decrease in inflammatory cytokines and
proinflammatory mediators, reduced infiltration of lymphocytes including T cells, and
preservation of intestinal architecture and the presence of APC protein in intestinal epithelial …
The intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not been addressed previously to our knowledge. Ablation of IL-17A significantly reduced tumor development in mice bearing a heterozygote mutation in the adenomatous polyposis coli (APC) gene (ApcMin/+ mice). There was also a decrease in inflammatory cytokines and proinflammatory mediators, reduced infiltration of lymphocytes including T cells, and preservation of intestinal architecture and the presence of APC protein in intestinal epithelial cells. Interestingly, IL-17A ablation also corrected immunological abnormalities such as splenomegaly and thymic atrophy in ApcMin/+ mice. CD4 T cells from ApcMin/+ mice showed hyperproliferative potential in vitro and in vivo and increased levels of IL-17A and IL-10. The effector CD4 T cells from ApcMin/+ mice were more resistant to regulatory T cell–mediated suppression. Finally, these CD4 T cells induced colitis in immunodeficient mice upon adoptive transfer, whereas the ablation of IL-17A in CD4 T cells in ApcMin/+ mice completely abolished this pathogenic potential in vivo. Taken together, our results show that CD4 T cell–derived IL-17A promotes spontaneous intestinal tumorigenesis with altered functions of CD4 T cells in ApcMin/+ mice.
National Acad Sciences