Interleukin 21 controls tumour growth and tumour immunosurveillance in colitis-associated tumorigenesis in mice.

Abstract

BACKGROUND AND AIMS:

Colitis-associated tumorigenesis is a balance between proliferation of tumour cells and tumour immunosurveillance. The role of T-helper-cell-derived cytokines in tumour growth is not fully understood. In this study the authors investigated the influence of interleukin (IL) 21 on intestinal tumorigenesis.

METHODS:

Chronic colitis was induced in IL-21(-/-) and littermate control wild-type mice with three cycles of 1.5% dextran sulphate sodium (DSS) over 7 days followed by 7 days of drinking water. Mice received an azoxymethane injection on day 0 of DSS-colitis to induce tumorigenesis. Immunohistochemistry was performed on inflamed and tumour-bearing areas of colons. Cytokine expression of isolated colonic CD4 T cells was determined by ELISA. Cytotoxic capacity of isolated colonic CD8 T cells targeting tumour cells was evaluated by flow cytometry and quantitative cytotoxicity assay. Apoptosis of tumour cells was determined by TUNEL assay of colonic sections.

RESULTS:

Increasing expression of IL-21 was observed in chronic colitis, which showed functional importance, since IL-21 deficiency prevented chronic DSS-colitis development. Further, in the absence of IL-21, significantly fewer tumour nodules were detected, despite a similar extent of intestinal inflammation. In wild-type mice, 8.6±1.9 tumour nodules were found compared with 1.0±1.2 in IL-21-deficient mice. In tumour-bearing IL-21-deficient mice, intestinal inflammation was restored and partly dependent on interferon (IFN)-γ, whereas the inflammation in wild-type mice showed high IL-17A concentrations. In these rare tumours in IL-21-deficient mice, tumour cell proliferation (Ki-67) was decreased, while cell apoptosis was increased, compared with wild-type mice. Increased IFNγ expression in tumour-bearing IL-21-deficient mice led to increased tumour immunosurveillance mediated by cytotoxic CD8CD103 T cells targeting E-cadherin(+) colonic tumour cells and therefore limited tumour growth.

CONCLUSION:

These results indicate that IL-21 orchestrates colitis-associated tumorigenesis, leading to the hypothesis that high IFNγ and low IL-17A expression reduces tumour cell proliferation and increases tumour immunosurveillance.

• Authors: Dominik Jauch, Maria Martin, Gabriela Schiechl, Rebecca Kesselring, Hans Jürgen Schlitt, Edward K Geissler, Stefan Fichtner-Feigl
• Journal: Gut (Gut) Vol. 60 Issue 12 Pg. 1678-86 (Dec 2011) ISSN: 1468-3288 [Electronic] England
• PMID: 21948944 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukins
• Interferon-gamma
• Dextran Sulfate
• interleukin-21

Topics

• Animals
• CD8-Positive T-Lymphocytes (physiology)
• Colitis (chemically induced, complications, immunology)
• Colon (chemistry, immunology)
• Colonic Neoplasms (etiology, immunology)
• Cytotoxicity Tests, Immunologic
• Dextran Sulfate (pharmacology)
• Immunologic Surveillance (physiology)
• Interferon-gamma (physiology)
• Interleukins (analysis, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monitoring, Immunologic