IL-22 possesses the ability to induce both STAT3-mediated expression of regulatory molecules (7
) and ERK-mediated expression of proinflammatory molecules (e.g., IL-8) (8
). The opposing effects of IL-22 have made it difficult to predict the role of IL-22 in IBD. We herein demonstrate that IL-22 contributes to rapid amelioration of local inflammation associated with a Th2-mediated colitis through activation of STAT3 in CECs. STAT3-mediated activation of acquired immune responses is well known as playing a pathogenic role in colitis by enhancing the survival of pathogenic T cells (37
). In contrast, STAT3-mediated activation of innate immune responses contributes to the suppression of colitis, as indicated by the spontaneous development of colitis in mice in which STAT3 is extinguished only in innate cells such as CECs or macrophages (40
). Since IL-22 specifically targets innate immune pathways (7
), selective activation of STAT3 in CECs but not acquired immune cells by IL-22 may contribute to amelioration of chronic Th2-mediated colitis.
IL-22 has previously been demonstrated to stimulate keratinocytes and CEC lines to produce several regulatory molecules, such as IL-10, SOCS3, and antibacterial peptides (β-defensin 2, psoriasin, calgranulins A and B) (7
). In addition, we herein demonstrate what we believe is a novel function of IL-22. IL-22 contributes to the improvement of colitis-associated mucus layer destruction associated with goblet cell depletion by enhancing the production of membrane-bound mucins (Muc1, -3, -10, and -13). Membrane-bound mucins form a static external barrier at the epithelial surface and are stored in goblet cell vacuoles (13
). Importantly, our studies suggest that the enhanced mucus barrier formation participates in the IL-22–mediated attenuation of Th2-mediated colitis. Indeed, recent studies have indicated that Muc2 and Muc3 contribute to the suppression of experimental colitis (33
). In addition, a more recent study clearly demonstrated a critical role of intestinal mucus layer for the suppression of colitis (44
). UC, which is characterized by a thin mucin layer in association with goblet cell depletion, exhibits strong expression of Muc2 and Muc4 and low expression of Muc1 and Muc3 (13
). Therefore, it is possible that insufficient production of IL-22 may facilitate goblet cell depletion and impair mucus layer formation in UC. Goblet cells specifically produce not only Muc but also other molecules involved in both regulation (e.g., trefoil factor) (45
) and exacerbation (e.g., resistan-like β [RELMβ]) (46
) of colitis. Interestingly, IL-22 downregulated the expression of goblet cell–derived RELMβ, a potential pathogenic goblet cell product (K. Sugimoto, unpublished observations).
Accumulating data in experimental IBD models have suggested the involvement of both common and distinct mechanisms of pathogenesis in UC versus CD. Experimental chronic UC-like disease is significantly contributed to by Th2 cytokines (14
). In contrast, IL-23/IL-17 pathways have recently been shown to play a pathogenic role in experimental CD-like diseases (15
). The relevance of the data from experimental colitis models to human CD is supported by recent studies showing a negative association of IL-23 receptor polymorphisms to the development of IBD (49
). Interestingly, IL-22, which is preferentially expressed by Th17 cells (4
), is significantly increased in CD patients in comparison with UC patients (8
). Thus, Th17 cells may be responsible for both deleterious effects through IL-17 production and beneficial effects through IL-22 production through an increase of mucus production. Indeed, a recent study has demonstrated a contribution of the Th17 subset in the suppression of a Th2-mediated asthma model that is characterized by dysregulated mucus production in the trachea (50
We developed a novel microinjection-based local gene-delivery system that allowed the targeting of inflamed mucosa and supplementation of local IL-22 expression restricted within the delivered site. Microbial-mediated in vivo gene delivery using adenovirus or L. lactis
has been used to cause local overexpression of some molecules in the intestine (22
). However, it may be difficult to avoid certain risks in these approaches, e.g., unwanted immune stimulation by virus-like particles or expression of genes of interest throughout the entire intestine by enteric bacteria–mediated gene delivery. Alternatively, our microinjection-based gene-delivery approach has several advantages. These include the restricted expression of the gene of interest to the injection site, transient expression (less than 4 weeks), and utilization of potentially harmless carriers as compared with microorganisms. Therefore, it is likely that potential side effects are minimized. In humans, such microinjection-based local gene delivery may be performed via endoscopy.
In summary, we provide an unexpected insight into the role of the Th17 cytokine IL-22 in Th2-mediated chronic colitis of TCRαKO mice. IL-22 stimulates mucus production and goblet cell restitution under intestinal inflammatory conditions and also contributes to the rapid attenuation of this inflammation. In addition, we describe a newly established local gene-delivery approach that is capable of targeting inflamed mucosa and may provide a means to developing a new therapeutic strategy for treating mucosal inflammation.