Interleukin-33 and inflammatory bowel diseases: lessons from human studies

Abstract

Interleukin- (IL-) 33 is a widely expressed cytokine present in different cell types, such as epithelial, mesenchymal, and inflammatory cells, supporting a predominant role in innate immunity. IL-33 can function as a proinflammatory cytokine inducing Th2 type of immune response being involved with the defense against parasitic infections of the gastrointestinal tract. In addition, it has been proposed that IL-33 can act as a signaling molecule alerting the immune system of danger or tissue damage. Recently, in the intestinal mucosa, overexpression of IL-33 has been reported in samples from patients with inflammatory bowel diseases (IBD). This review highlights the available data regarding IL-33 in human IBD and discusses emerging roles for IL-33 as a key modulator of intestinal inflammation.

Figure 1

Representation of IL-33 function in the gastrointestinal mucosa. Full-length IL-33 (30 kDa) is released by a wide range of different cell types, represented here by enterocytes, fibroblasts, and macrophages. IL-33 interacts with lamina propria T cells and determines the production of IL-4, IL-5, and IL-13. IL-13 enhances mucus production by goblet cells, while IL-5 activates eosinophils and B cells, and IL-4 induces Th2 polarization. IL-33 can also activate eosinophils and macrophages, further contributing to a Th2 response in the lamina propria. Neutrophil can release a lighter structure of IL-33 (18–22 kDa), which is known to be more active than the 30 kDa protein. During cellular apoptosis, IL-33 can be cleaved by caspases 3 and 7, generating a 20–22 kDa molecule, a potentially less active protein.

Figure 2

Representation of IL-33 pathway in T-helper cells. IL-33 interacts with ST2L and the receptor accessory protein IL-RAcP in the membrane. Both possess a domain TIR that allows interacting with MyD88, IRAK1/4, TRAF6, and TAK1 in the cytosol. These intracellular signaling molecules determine IκK inactivation by phosphorylation and degradation in proteasome complex. The consequent NFκB activation results in the production of Th2 cytokines.