Abstract
Initially described as Th2 promoter cytokine, more recently, IL-33 has been recognized as an alarmin, mainly in epithelial and endothelial cells. While localized in the nucleus acting as a gene regulator, it can be also released after injury, stress or inflammatory cell death. As proinflammatory signal, IL-33 binds to the surface receptor ST2, which enhances mast cell, Th2, regulatory T cell, and innate lymphoid cell type 2 functions. Besides these Th2 roles, free IL-33 can activate CD8+ T cells during ongoing Th1 immune responses to potentiate its cytotoxic function. Celiac Disease (CD) is a chronic inflammatory disorder characterized by a predominant Th1 response leading to multiple pathways of mucosal damage in the proximal small intestine. By immunofluorescence and western blot analysis of duodenal tissues, we found an increased expression of IL-33 in duodenal mucosa of active CD (ACD) patients. Particularly, locally digested IL-33 releases active 18/21kDa fragments which can contribute to expand the proinflammatory signal. Endothelial (CD31+) and mesenchymal, myofibroblast and pericyte cells from microvascular structures in villi and crypts, showed IL-33 nuclear location; while B cells (CD20+) showed a strong cytoplasmic staining. Both ST2 forms, ST2L and sST2, were also upregulated in duodenal mucosa of CD patients. This was accompanied by increased number of CD8+ST2+ T cells and the expression of T-bet in some ST2+ intraepithelial lymphocytes and lamina propria cells. IL-33 and sST2 mRNA levels correlated with IRF1, an IFN induced factor relevant in responses to viral infections and interferon mediated proinflammatory responses highly represented in duodenal tissues in ACD. These findings highlight the potential contribution of IL-33 and its fragments to exacerbate the proinflammatory circuit and potentiate the cytotoxic activity of CD8+ T cells in CD pathology.
Highlights
Interleukin-33 (IL-33) is a 30 kDa protein belonging to the IL-1 family, that is mainly expressed in the nucleus of fibroblasts, subepithelial myofibroblasts (SEMFs), keratinocytes, adipocytes, endothelial and epithelial cells from different tissues [1]
Since one of the most important events in IL-33 signaling is its release into the extracellular medium, we analyzed IL-33 and its decoy receptor sST2 in serum samples of a local pediatric and adult populations of active Celiac Disease (CD) patients (ACD) and non-CD (NC) controls
ACACTCCAGGATCAGTCTTG GACTACATCTTCTCCAGGTAGCAT CAATTTAAGCAGCAGAGAAGCTCC TCTCATAGATGGTCAATGCGGCGT ATGCTCTTCGACCTCGAAAC TCAGACAAGGCTTGGCAACCCA TAGCATCTCGGCTGGACTTCGA CCAAGACCCAGGCATACTTGA. These findings demonstrate that a cellular source of IL-33 and sST2 is actively releasing these molecules in ACD patients
Summary
Interleukin-33 (IL-33) is a 30 kDa protein belonging to the IL-1 family, that is mainly expressed in the nucleus of fibroblasts, subepithelial myofibroblasts (SEMFs), keratinocytes, adipocytes, endothelial and epithelial cells from different tissues [1]. When cells die by apoptosis, IL-33 is cleaved by active caspase 3 or 7, producing a non-bioactive form. Enzymes secreted by neutrophils or mast cells like cathepsin G, neutrophil elastase, tryptase or chymase may cleave free IL-33 producing diverse mature fragments of 18 to 21 kDa, having stronger bioactivities than the full-length form [3, 4]. Soluble IL-33 was initially linked to a strong capacity to stimulate Type 2 immune responses, through its actions on Th2, Mast cells and ILC2 cell [5,6,7]. Increasing evidence demonstrated that IL-33 is able to promote Type-1 immune responses [8], CD8+ T cytotoxic cells [9] and invariant NKT cells activation [10], as well as, support regulatory T (Treg) cell responses [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
