It has been previously demonstrated that IL-22 plays a protective role within many organs, such as anti-microbial defense, regeneration, and protection against injury [36, 37]. These findings are based on the distribution of two reporters: IL-22R1 (IL-22RA1) and IL-10R2. IL-22R1 is located primarily in the skin, digestive tract (including pancreas and liver), lung, and kidney, while IL-10R2 is ubiquitously expressed [28, 36]. IL-22 acts as a protector in intestinal mucosal healing through multiple signaling activation steps. In an intestinal infection with C. rodentium, IL-22 is produced earlier than IL-17A and it plays a decisive role, whereas IL-17A does not . Moreover, Sugimoto et al. demonstrated that IL-22 contributes to rapid amelioration of local inflammation associated with Th2-mediated colitis . Additionally, studies in genetically engineered mice have demonstrated that epithelial STAT3 activation in dextran sodium sulfate colitis is dependent upon IL-22 rather than IL-6, and that both IL-22 and epithelial STAT3 is important in wound-healing experiments in vivo . Therefore, according to these studies, most of the protective roles of IL-22 in the intestinal tract are linked to STAT3 in IECs, a pleiotropic transcription factor with important functionality in cytokine signaling in a variety of tissues [41, 42]. However, IL-22 has also been considered an inflammatory driver in IBD based upon both clinical evidence and mouse model data. Highly elevated serum levels and a potential systemic role for IL-22 have been demonstrated to correlate with disease severity in patients with Crohn’s disease (CD). In 2005 it was shown that IL-22 was much higher in UC compared to CD, and a study of human IBD revealed that IL-22 derived from activated T cells acts on human colonic subepithelial myofibroblasts to stimulate secretion of proinflammatory cytokines and matrix-degrading molecules, thus demonstrating its proinflammatory/remodeling role in IBD . Similar outcomes have been obtained from a colitis mouse model, indicating that highly elevated IL-22 expression was an inflammation driver in either a direct or indirect manner [39, 43]. More recently, the role of IL-22 in mouse IBD and colon cancer have been clarified by Huber et al. which indicated that the ratio of IL-22/IL-22BP is critical in regulating intestinal tissue repair and tumorigenesis in the colon .
As discussed above, STAT3 activation by IL-22 plays both protective and inflammatory driver roles in human IBD, which is similar to what occurs in the liver. IL-22 demonstrates a directly protective role in acute liver injury, which has been demonstrated by both the Radaeva and Zenewicz research groups. However, the authors also hypothesized that the protective effect of IL-22 was due to activation of STAT3, and that its anti-apoptotic and regeneration promoting effect potentially contributes to the development of HCCs [45, 46]. This hypothesis was verified by both us and Park et al. recently, and it has been revealed that IL-22 exhibits opposing short-term and long-term effects in the liver which in turn promote cell proliferation, survival, metastasis, and transformation from chronic hepatitis to HCC [34, 47]. Therefore, we investigated whether the opposing effects of short-term and long-term IL-22 activated STAT3 exist in the human intestinal tract. Initially, our investigation confirmed that massive levels of IL-22 were present in the UC tissues of the Chinese population. Secondly, we reported for the first time that excessive IL-22 also was present in human colon cancer. Furthermore, up-regulation of IL-22 in TILs derived from human CC was associated with the activation of STAT3 and exhibited tumor promotion and enhancement of metastasis in both in vitro and in vivo model.
The tumor microenvironment is composed of tumor cells, macrophages, and immunocytes etc. where the interactions between these cells involves their secreted cytokines and consists of a free-forward loop with persistent activation of STAT3 enabling promotion of tumor growth . Consistent with IL-23 and IL-22RA1, an IL-22 feed-forward loop in the CC or UC microenvironment has been demonstrated through our research. The IL-22 signal can be transmitted through a heterodimeric receptor complex that consists of IL-22R1 (IL-22RA1) and IL-10R2 [48, 49]. Unlike the ubiquitously expressed IL-10R2 chain, the IL-22RA1 chain was normally restricted to non-immune cells such as epithelial cells and hepatocytes . In correlation with overexpression of IL-22 in TILs of CC, IL-22RA1 is also overexpressed in colon cancer cells and in IECs of UC, which ensures the transmission of the IL-22 signal. Pro-tumor cytokine IL-23, which is also regulated by STAT3 [51, 52], is over expressed in CC and UC. Excessive expression of IL-23 plus TNF-α, IL-6, and IL-1β, which have already been demonstrated to be overexpressed in human CC, composed a milieu for infiltrated naive lymphocytes which were also enrolled by STAT3 activation to differentiate to Th17 cells expressing IL-22 [20–23]. In this study, we transplanted this IL-22 related tumor microenvironment beneath the skin of nude mice. The proliferation and metastasis enhancing effects of this free-forward loop were confirmed, and proliferation associated cyclinD1, cell survival associated BCL-XL, and metastasis associated VEGF were all upregulated and mediated by STAT3 activation, which was demonstrated by phosphorylation of S727 residue [9, 52]. Furthermore, these tumor growth and metastasis promotional effects of IL-22 were demonstrated to occur in a dose-dependent manner when various tumor microenvironments were transplanted with a range of IL-22 levels. We investigated more precise and accurate mechanisms with in vitro studies utilizing the IL-22 and IL-6 depletion assay; cell survival and tumor promotion was eliminated when IL-22 was blocked based upon the attenuated activation of STAT3 which is similar to IL-6, Moreover, the specialty of IL-22 effect through STAT3 signaling was verified by using STAT3 inhibitor WP1066.