In this review, we will summarize the roles and mechanisms of IL-33 in IBD, which is essential to understand the pathogenesis of IBD and determine potential therapies.
IL-33, a cytokine upregulated in inflammatory bowel disease and helminth infection, induces intestinal goblet cells, but the mechanism remains unclear.
Over-expression of full-length IL33 by IEC did not promote gut inflammation, but induced expression of genes in the IEC and lamina propria lymphocytes (LPL) that correlated negatively with genes expressed in inflammatory bowel diseases (IBD).
Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis.
Although IL-33 and its receptor ST2/ILRL1 are known to be increased and associated with IBD, studies using animal models of colitis to address the mechanism have yielded ambiguous results, suggesting both pathogenic and protective functions.
Our data thus demonstrate that HIF-1α-dependent IL-33 in IEC functions as a regulatory cytokine in inflamed mucosa of IBD, thereby regulating the intestinal inflammation and maintaining mucosal homeostasis.
Serum levels of IL-33 are increased in inflammatory bowel diseases (IBD), suggesting that IL-33 is involved in the pathogenesis of IBD, although its role is not clear.
We found that patients with IBD show decreased serum levels of IL-33 compared with healthy individuals and that IL-33 can attenuate colitis and aid tissue repair in mice.
Animal models of IBD were subsequently utilized in order to mechanistically determine the precise role of IL-33 in chronic intestinal inflammation, without, however, reaching conclusive evidence demonstrating whether IL-33 is pathogenic or protective.
Upon genotype-phenotype evaluation, an increased frequency of extensive colitis in adult UC (P = 0.019) and in steroid-responsive pediatric patients (P = 0.024) carrying the IL-33rs3939286 risk genotype, was observed. mRNA expression of IL-33 and IL1RL1 in inflamed IBD biopsy samples was significantly increased.
In the present study, we report that basophils can be detected in the mucosa of Th17-associated lung and inflammatory bowel disease and accumulate in inflamed colons containing large quantities of IL-33.
The recent findings in IBD include the increasing number of IBD susceptibility genes, the demonstration that NOD2 and ATG16L1 are linked in one functional pathway and the role of IL-33/ST2 in colitis.