Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis.

Abstract

Inflammatory bowel disease increases the risk of developing colon cancer. Interleukin (IL-) 37 is a fundamental inhibitor of innate immunity by reducing systemic and local inflammation. IL-37 protein is expressed in healthy and diseased bowel and liver tissue. Here, we tested whether transgenic expression of human IL-37 protects IL-10 deficient (IL-10KO) mice from chronic colitis. IL-37tg mice were crossbred with IL-10KO mice. Homozygous IL-10KO/IL-37tg and IL10KO drank 2% dextran sulfate sodium (DSS) in water for 5 days to induce mild colitis. Colon carcinogenesis was triggered by intragastric administration of celecoxib. Endpoints were clinical parameters of colitis, cytokine responses in LPS-stimulated whole blood and explanted colon specimen and qPCR analysis of colon biopsies. Colon inflammation and number of adenoma-carcinoma were analyzed by histology. During the DSS-induction phase IL-10KO and IL-10KO/IL-37tg mice had a similar weight loss due to mild acute colitis. From day 115 there was a significantly improved weight gain in IL-10KO/IL37-tg mice, though colon length was similar. After ex vivo LPS stimulation whole blood of IL-10KO/IL-37tg compared to IL-10KO mice released less IL-6, IL-17, IFNγ, and TNFα and ex vivo colon cultures showed reduced IL-6 production both indicative of reduced inflammatory conditions under the influence of IL-37. Six out of 10 IL-10KO mice developed colon adenoma and carcinoma. Only one adenoma but no carcinoma was detected in colons of IL-10KO/IL-37tg mice. In conclusion, IL-37 transgene expression protects IL-10KO mice from colon carcinogenesis. It remains unclear whether IL-37 has direct tumor suppressing properties.

• Authors: Steffeni Mountford, Andrea Ringleb, Rahel Schwaiger, Doris Mayr, Sebastian Kobold, Charles A Dinarello, Philip Bufler
• Journal: Frontiers in immunology (Front Immunol) Vol. 10 Pg. 2632 ( 2019) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 31781119 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Mountford, Ringleb, Schwaiger, Mayr, Kobold, Dinarello and Bufler.

Chemical References

• IL37 protein, human
• Interleukin-1
• Interleukin-10
• Dextran Sulfate

Topics

• Animals
• Chronic Disease
• Colitis (chemically induced, immunology, pathology)
• Colon (pathology)
• Dextran Sulfate
• Interleukin-1 (genetics, immunology)
• Interleukin-10 (genetics)
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Transgenes