Involvement of interleukin-21 in the regulation of colitis-associated colon cancer

Abstract

IL-21 expression is increased in the gut of patients with colitis-associated colon cancer, and genetic ablation or antibody neutralization of IL-21 reduces tumor size and inflammation in mice treated with dextran sulfate sodium and azoxymethane.

Signal Transducer and Activator of Transcription 3 - A Promising Target in Colitis-Associated Cancer

“…Excessive evidence supports that, elevated levels of IL-21 in the gut has deleterious consequences for the host. DSS or TNBS-induced wild-type colitis mice produce high level of IL-21; also IL-21-knockout mice are largely protected against disease in both models (Fina et al, 2008;Stolfi et al, 2011). IL-21 was highly expressed in human CRC patients and IL-21-deficient mice were resistant to CAC induced with AOM and DSS.…”

“…IL-21, like IL-6 and IL-17A, is a powerful activator of the transcription factor STAT3 (Caprioli et al, 2008;Hirahara et al, 2010), which is a critical modulator of chronic inflammation (Atreya et al, 2008). Absence of IL-21 reduced STAT3 Activation and reduced the expression of Bcl-xL, a STAT3-induced anti-apoptotic protein in tumor and stromal cells (Stolfi et al, 2011).…”

Deficiency of the immunostimulatory cytokine IL-21 promotes intestinal neoplasia via dysregulation of the Th1/Th17 axis

“…4,17 Our results, however, contradict previous studies examining the relationship between IL-21 and intestinal tumorigenesis induced by dextran sulfate sodium (DSS) and azoxymethane (AOM). 10,11,18 DSS and AOM are commonly used to mimic colitis-associated colon cancer. Notably, one study used AOM alone in APC MIN/C mice.…”

“…1 IL-21 is involved in the proliferation of T and B cells as well as the cytotoxic activity of T and NK cells, 2,3 IL-21 was initially viewed as a potential anticancer treatment for its enhancement of the Th1 pathway 4,5 without a compensatory increase in regulatory T cells (Tregs). 6,7 More recently, however, IL-21 has been reported to be associated with the promotion of Th17 pathway inflammation, 8,9 and its inhibition has been associated with improvement in colitis-associated colorectal cancer, 10,11 The immune mechanisms in the development of colitis-associated colorectal cancer and sporadic colorectal cancer likely differ. In sporadic colorectal cancer, there is a balance between tumor-promoting inflammation and antitumor immunity, whereas in colitisassociated colorectal cancer, the immune system appears to have a mostly inflammatory and pro-tumorigenic role.…”

Current overview of colitis-associated colorectal cancer

“…IL-21 is over-produced in the colonic mucosa of IBD patients, where it regulates Th-17 cell responses [39,40]. High levels of IL-21 have been observed in the intestine of UC patients with CACRC [41] and therefore it has been defined as a key cytokine for promotion of CACRC [42].…”