Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis

Abstract

Interleukin (IL)-21 triggers inflammatory signals that contribute to the growth of neoplastic cells in mouse models of colitis-associated colorectal cancer (CRC). Because most CRCs are sporadic and arise in the absence of overt inflammation we have investigated the role of IL-21 in these tumors in mouse and man. IL-21 was highly expressed in human sporadic CRC and produced mostly by IFN-γ-expressing T-bet/RORγt double-positive CD3+CD8− cells. Stimulation of human CRC cell lines with IL-21 did not directly activate the oncogenic transcription factors STAT3 and NF-kB and did not affect CRC cell proliferation and survival. In contrast, IL-21 modulated the production of protumorigenic factors by human tumor infiltrating T cells. IL-21 was upregulated in the neoplastic areas, as compared with non-tumor mucosa, of Apcmin/+ mice, and genetic ablation of IL-21 in such mice resulted in a marked decrease of both tumor incidence and size. IL-21 deficiency was associated with reduced STAT3/NF-kB activation in both immune cells and neoplastic cells, diminished synthesis of protumorigenic cytokines (that is, IL-17A, IL-22, TNF-α and IL-6), downregulation of COX-2/PGE2 pathway and decreased angiogenesis in the lesions of Apcmin/+ mice. Altogether, data suggest that IL-21 promotes a protumorigenic inflammatory circuit that ultimately sustains the development of sporadic CRC.

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

“…18 In contrast to the downregulation of the Th1-associated gene profile in IL-21 deficient mice, we found increased expression of pro-inflammatory Th17 genes with a greater than 2-fold increase in expression of the prototypical Th17 transcription factor RORgt and a greater than 5-fold increase in expression of the eponymous cytokine IL-17A at 15 weeks. The role of IL-17A in promoting carcinogenesis in the APC MIN/C model has previously been demonstrated, 16,21 and genes associated with Th17 polarization have been correlated with decreased survival in human colorectal cancer.…”

“…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.…”

“…Notably, one study used AOM alone in APC MIN/C mice. 18 The differences between the APC MIN/C and the AOM-APC MIN/C model could conceivably be related to the fact that in the AOM-APC MIN/C model, colon tumors were examined, whereas in the APC MIN/C model, the preponderance of the adenomas develop in the small intestine. More likely, however, the differences are related to administration of AOM, which has been shown to induce colitis-associated crypt changes in the colon.…”

“…Our results are also surprising given that reduced expression of IL-17A was seen in tumors from IL-21-deficient AOM-APC MIN/C mice. 18 As discussed further above, we believe the differences in the APC MIN/C and the AOM-APC MIN/C models are likely related to the use of AOM, which has been shown to induce inflammatory changes. Expression of genes associated with the Th2 and Treg pathways was essentially unchanged between the groups.…”

Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

“…IL-21 exerts its effect on a broad range of cell types. Increasing evidence shows that IL-21 potently regulates innate and adaptive immune response (6)(7)(8). Furthermore, the role of IL-21 in angiogenesis has also been studied (9,10).…”