title: Involvement of interleukin-21 in the regulation of colitis-associated colon cancer.
abstract: Chronic inflammation is a major driving force in the development of cancer in many tissues, but the array of factors involved in this neoplastic transformation are not well understood. We have investigated the role of interleukin (IL)-21 in colitis-associated colon cancer (CAC), as this cytokine is overexpressed in the gut mucosa of patients with ulcerative colitis (UC), a chronic inflammatory disease associated with colon cancer. IL-21 was increased in the gut of patients with UC-associated colon cancer, and in mice with CAC induced by azoxymethane (AOM) and dextran sulfate sodium (DSS). After AOM+DSS treatment, IL-21 KO mice showed reduced mucosal damage, reduced infiltration of T cells, and diminished production of IL-6 and IL-17A. IL-21-deficient mice also developed fewer and smaller tumors compared with wild-type (WT) mice. Absence of IL-21 reduced signal transducer and activator of transcription 3 activation in tumor and stromal cells. Administration of a neutralizing IL-21 antibody to WT mice after the last DSS cycle decreased the colonic T cell infiltrate and the production of IL-6 and IL-17A and reduced the number of tumors. These observations indicate that IL-21 amplifies an inflammatory milieu that promotes CAC, and suggest that IL-21 blockade may be useful in reducing the risk of UC-associated colon cancer.
authors: Gastroenterology Unit, Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
authors: Carmine
authors: C
authors: Stolfi
authors: Angelamaria
authors: A
authors: Rizzo
authors: Eleonora
authors: E
authors: Franzè
authors: Angela
authors: A
authors: Rotondi
authors: Massimo Claudio
authors: MC
authors: Fantini
authors: Massimiliano
authors: M
authors: Sarra
authors: Roberta
authors: R
authors: Caruso
authors: Ivan
authors: I
authors: Monteleone
authors: Pierpaolo
authors: P
authors: Sileri
authors: Luana
authors: L
authors: Franceschilli
authors: Flavio
authors: F
authors: Caprioli
authors: Stefano
authors: S
authors: Ferrero
authors: Thomas T
authors: TT
authors: MacDonald
authors: Francesco
authors: F
authors: Pallone
authors: Giovanni
authors: G
authors: Monteleone
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000009:adverse effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000166:cytology / Q000276:immunology / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate / Q000009:adverse effects; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D002273:Carcinogens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016264:Dextran Sulfate; D000098546:Interleukin-21; D001397:Azoxymethane