title: 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.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA; IRCCS Policlinico San Donato, Gastroenterology and Gastrointestinal Endoscopy Unit, San Donato Milanese, Italy; University of Milan School of Medicine, Medical and Surgical Sciences, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pastorelli
authors.forename: Carlo
authors.initials: C
authors.lastname: De Salvo
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Cominelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vecchi
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Pizarro