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.
| Original language | English |
|---|---|
| Pages (from-to) | 2279-2290 |
| Number of pages | 12 |
| Journal | Journal of Experimental Medicine |
| Volume | 208 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Oct 24 2011 |
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ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
Cite this
Involvement of interleukin-21 in the regulation of colitis-associated colon cancer. / Stolfi, Carmine; Rizzo, Angelamaria; Franzè, Eleonora; Rotondi, Angela; Fantini, Massimo Claudio; Sarra, Massimiliano; Caruso, Roberta; Monteleone, Ivan; Sileri, Pierpaolo; Franceschilli, Luana; Caprioli, Flavio; Ferrero, Stefano; MacDonald, Thomas T.; Pallone, Francesco; Monteleone, Giovanni.
In: Journal of Experimental Medicine, Vol. 208, No. 11, 24.10.2011, p. 2279-2290.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Involvement of interleukin-21 in the regulation of colitis-associated colon cancer
AU - Stolfi, Carmine
AU - Rizzo, Angelamaria
AU - Franzè, Eleonora
AU - Rotondi, Angela
AU - Fantini, Massimo Claudio
AU - Sarra, Massimiliano
AU - Caruso, Roberta
AU - Monteleone, Ivan
AU - Sileri, Pierpaolo
AU - Franceschilli, Luana
AU - Caprioli, Flavio
AU - Ferrero, Stefano
AU - MacDonald, Thomas T.
AU - Pallone, Francesco
AU - Monteleone, Giovanni
PY - 2011/10/24
Y1 - 2011/10/24
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20111106
DO - 10.1084/jem.20111106
M3 - Article
VL - 208
SP - 2279
EP - 2290
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 11
ER -