Novel cytokine signaling pathways in inflammatory bowel disease: insight into the dichotomous functions of IL-33 during chronic intestinal inflammation

Abstract

In 2010, four independent groups almost simultaneously reported the association of the novel interleukin-1 (IL-1) family member, IL-33, with inflammatory bowel disease (IBD). The findings were remarkably consistent and demonstrated that IL-33 is markedly upregulated in, and specific to, ulcerative colitis (UC). In addition, although a variety of gut-associated immune cell subsets express IL-33, the primary source appears to be the intestinal epithelium. IL-33's receptor, ST2, a formerly orphaned IL-1 receptor-related protein, was also found to be increased in UC patients, although the cellular source of ST2 appears to be somewhat more ambiguous. In fact, emerging evidence indicates that the IL-33/ST2 axis plays a critical role in several other chronic inflammatory and immune disorders. In the gut, IL-33 has been shown to be important in the clearance of intestinal parasites, and inducing epithelial cell hyperplasia, mucus production and mucosal eosinophilic infiltration. However, despite the established trend of increased IL-33 and ST2 expression during IBD, specifically UC, the precise pathophysiologic relevance of these findings has yet to be determined. Interestingly, IL-33 has the ability to potentiate pathogenic Th2 and Th17 responses in gut-associated lymphoid tissues, while also promoting healing of damaged mucosa following inflammatory insults. Indeed, further mechanistic studies are warranted to confirm the possible dichotomous functions of IL-33 during chronic intestinal inflammation and better define its precise role in the pathogenesis of IBD. Herein, we discuss what is currently known about IL-33/ST2 in the gut and speculate as to the potential role of the IL-33/ST2 system in IBD.

IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13 dependent

“…IL-33 is a key immune modulator in the gut mucosa and has been implicated in host protective immunity against enteric nematode infection and gut inflammatory pathologies such as ulcerative colitis (16,29,30). The present study demonstrated that IL-33 promotes potent type 2 immunity in the intestine.…”

IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin–EGFR interactions

“…Expression of IL-33 and its receptor ST2 has been shown to be dysregulated in IBD patients (10,12,13,37). However, whether IL-33 plays a tissue-protective or pathologic role in the colonic intestinal mucosa during disease remains controversial (10,11,30,31,(37)(38)(39), and the cellular and molecular mechanisms acting downstream of IL-33 to regulate disease are poorly defined.…”

“…However, whether IL-33 plays a tissue-protective or pathologic role in the colonic intestinal mucosa during disease remains controversial (10,11,30,31,(37)(38)(39), and the cellular and molecular mechanisms acting downstream of IL-33 to regulate disease are poorly defined. Here we identify the ILC2-AREG-EGFR axis as one mechanism by which IL-33 orchestrates intestinal tissue protection, associated with promotion of AREG-dependent mucin production.…”

“…Here we identify the ILC2-AREG-EGFR axis as one mechanism by which IL-33 orchestrates intestinal tissue protection, associated with promotion of AREG-dependent mucin production. IL-33 is a wellappreciated regulator of mucin responses in multiple inflammatory settings (10,11,37), but in colitis this process is largely thought to act through Notch-and IL-13-dependent signaling (31,39). Our data indicate that ILC2-intrinsic AREG is an additional contributor to regulation of mucin responses.…”

Interleukin-33 Ameliorates Experimental Colitis through Promoting Th2/Foxp3+ Regulatory T-Cell Responses in Mice

“…In contrast, IL-33 reduces the development of atherosclerosis (17), attenuates sepsis (34) and allows susceptible mice to expel the parasite (35). Indeed, the IL-33/ST2 system also plays a dichotomous role in inflammatory bowel disease pathogenesis (36,37), and the exact role of this axis needs to be further defined. Here, we show that IL-33 was markedly increased in the mice with TNBS-induced colitis, which mimics human CD.…”