Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis
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 expr...
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doaj-9037377594694bd198eea3d5eb1732bc2020-11-25T01:46:19ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-11-011010.3389/fimmu.2019.02632499552Interleukin-37 Inhibits Colon Carcinogensis During Chronic ColitisSteffeni Mountford0Andrea Ringleb1Rahel Schwaiger2Doris Mayr3Sebastian Kobold4Sebastian Kobold5Charles A. Dinarello6Philip Bufler7Philip Bufler8Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, GermanyDepartment of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, GermanyDepartment of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, GermanyInstitute of Pathology, Ludwig-Maximilians-University, Munich, GermanyCenter for Integrated Protein Science Munich (CIPSM), Division of Clinical Pharmacology, Klinikum der Ludwig-Maximilians-Universität München, Munich, GermanyGerman Consortium for Translational Cancer Research (DKTK), Partner Site Munich, GermanyDepartment of Medicine and Immunology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, GermanyDepartment of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité Universitätsmedizin Berlin, Berlin, GermanyInflammatory 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.02632/fullchronic colitiscarcinogenesiscytokinesinflammationIL-37 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Steffeni Mountford Andrea Ringleb Rahel Schwaiger Doris Mayr Sebastian Kobold Sebastian Kobold Charles A. Dinarello Philip Bufler Philip Bufler |
spellingShingle |
Steffeni Mountford Andrea Ringleb Rahel Schwaiger Doris Mayr Sebastian Kobold Sebastian Kobold Charles A. Dinarello Philip Bufler Philip Bufler Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis Frontiers in Immunology chronic colitis carcinogenesis cytokines inflammation IL-37 |
author_facet |
Steffeni Mountford Andrea Ringleb Rahel Schwaiger Doris Mayr Sebastian Kobold Sebastian Kobold Charles A. Dinarello Philip Bufler Philip Bufler |
author_sort |
Steffeni Mountford |
title |
Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis |
title_short |
Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis |
title_full |
Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis |
title_fullStr |
Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis |
title_full_unstemmed |
Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis |
title_sort |
interleukin-37 inhibits colon carcinogensis during chronic colitis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2019-11-01 |
description |
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. |
topic |
chronic colitis carcinogenesis cytokines inflammation IL-37 |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2019.02632/full |
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