Emerging role of the interleukin (IL)-33/ST2 axis in gut mucosal wound healing and fibrosis

The role of interleukin (IL)-1 and its related cytokine family members is well established in the pathogenesis of several autoinflammatory and chronic immune disorders, including inflammatory bowel disease (IBD) [1]. IL-33, also known as IL-1F11, represents the most recently identified member of the IL-1Family, which also includes the classic cytokines IL-1α, IL-1β and IL-18. IL-33 is a protein with a dual function that can act both as a signaling cytokine as well as an intracellular nuclear factor, originally reported to be preferentially localized to the high endothelial venules of human tonsils, Peyer’s patches and lymph nodes [2]. More recent evidence suggests that IL-33 is widely distributed throughout various organ systems in the body, primarily expressed in nonhematopoietic cells, including fibroblasts, adipocytes, smooth muscle cells, endothelial cells, bronchial and intestinal epithelial cells (IEC) [3-5], but is also present in cells of hematopoietic origin, particularly in restricted populations of professional antigen-presenting cells, such as macrophages and dendritic cells [5].IL-33 exerts its biological effects through binding to its receptor, IL-1 receptor-like 1 (IL1RL1), also known as ST2 [5,6]. In the presence of IL-33, ST2 pairs with its coreceptor, the IL-1 receptor accessory protein (IL-1RAcP), and allows signaling through mitogen-activated protein kinase and NF-κB [5,7]. ST2 has been reported to be constitutively expressed in mast cells, as well as T helper (Th)2 lymphocytes in both mice and humans [5,8,9].Initially, IL-33 was associated with the development of Th2 immunity, based on the expression of its cell-bound receptor, ST2L (IL-1R4), in polarized Th2 lymphocytes and its ability to induce the production of Th2 cytokines (for example, IL-4, IL-5 and IL-13), in both in vitro and in vivo systems [5]. Moreover, exogenous administration of recombinant IL-33 in mice led to Th2-mediated immune responses, inducing eosinophilia, splenomegaly, gob