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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 12; pp. 5540 - 5544
• Main Authors: Chae, Wook-Jin, Gibson, Thomas F, Zelterman, Daniel, Hao, Liming, Henegariu, Octavian, Bothwell, Alfred L.M
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.03.2010; National Acad Sciences
• Subjects: Animals; Biological Sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Colitis; Cytokines; Cytokines - genetics; Epithelial cells; Genes, APC; Ileum; Inflammation; Inflammation Mediators - metabolism; Interleukin-17 - deficiency; Interleukin-17 - genetics; Interleukin-17 - physiology; Intestinal Neoplasms - etiology; Intestinal Neoplasms - genetics; Intestinal Neoplasms - immunology; Intestinal Neoplasms - pathology; Lymphocytes; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Mutation; Phenotype; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Rodents; Small intestine; Spleen; Spleen - immunology; Spleen - pathology; T cell receptors; T lymphocytes; Thymus Gland - immunology; Thymus Gland - pathology; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0912675107

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.