Clinical importance of IL-22 cascade in IBD

Abstract

IL-22 is a relatively new cytokine that is characterized by several unique biological properties. In the intestines, the effect of IL-22 is restricted mainly to non-lymphoid cells such as epithelial cells. Interestingly, the expression pattern and major cellular source of IL-22 have distinct difference between large and small intestines. IL-22 possesses an ability to constitutively activate STAT3 for promoting epithelial cell regeneration and reinforcing mucosal barrier integrity through stimulating the expression of anti-bacterial peptide and mucins. Of note, IL-22 is characterized as a two-faced cytokine that can play not only protective but also deleterious roles in the intestinal inflammation depending on the cytokine environment such as the expression levels of IL-23, T-bet, and IL-22 binding protein. Most importantly, clinical relevance of IL-22 to inflammatory bowel disease has been well highlighted. Mucosal healing, which represents the current therapeutic goal for IBD, can be induced by IL-22. Indeed, indigo naturalis, which can activate IL-22 pathway through Ahr, has been shown in a clinical trial to exhibit a strong therapeutic effect on ulcerative colitis. Despite the beneficial effect of IL-22, continuous activation of the IL-22 pathway increases the risk of colitis-associated cancer, particularly in patients with an extended history of IBD. This review article discusses how IL-22 regulates colitis, how beneficial versus deleterious effects of IL-22 is determined, and why IL-22 represents a promising target for IBD therapy.

Keywords: Ahr; IL-22BP; IL-23; Indigo naturalis; Mucus.

Fig. 1

Regulation of IL-22 functions: IL-22 can be produced by many cell types. The production of IL-22 is stimulated by Ahr, and RegIIIβ may have the ability to recruit IL-22-producing neutrophils. IL-22 then plays not only protective but also deleterious roles in intestinal inflammation depending on the cytokine environments. IL-1β and IL-23-medicated activation of epithelial cells may elicit the beneficial effect of IL-22, whereas hyper response of T cells to IL-23 for acquiring their ability to produce both IL-17 and IFN-γ may elicit the deleterious function of IL-22. The activity of IL-22 can be suppressed by an endogenous inhibitor IL-22BP that is produced by DCs, eosinophils, and CD4⁺ T cells. TNF-α stimulates the expression of IL-22BP in CD4⁺ T cells. Alternatively, formation of inflammasome and maturation of DCc may contribute for reducing the IL-22BP expression

Fig. 2

Clinical importance of IL-22 to IBD particularly UC: The clinical relevance of IL-22 can be highlighted by much basic and clinical evidence. For example, IL-22 can promote the mucosal healing in mice, which is a current major goal of IBD therapy. The majority of molecules induced by IL-22 are encoded by IBD susceptibility genes. In addition, IL-22 stimulates the production of calprotectin, which is a useful biomarker of IBD. Interestingly, the IL-22 pathway may provide a clue to resolve a long-standing etiological mystery that cigarette smoking is negatively associated with the development of UC and to further understand the carcinogenesis pathway of colitis-associated cancer. Importantly, a recent pilot study demonstrated the therapeutic effect of Ahr-activation capable of stimulating IL-22 production of mild-to-moderate UC