title: Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis.
abstract: IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. Recent evidence suggests that the IL-33/ST2 axis plays a critical role in several autoimmune and inflammatory disorders; however, its role in inflammatory bowel disease (IBD) has not been clearly defined. We characterized IL-33 and ST2 expression and modulation after conventional anti-TNF therapy in Crohn's disease and ulcerative colitis (UC) patients and investigated the role of IL-33 in SAMP1/YitFc (SAMP) mice, a mixed Th1/Th2 model of IBD. Our results showed a specific increase of mucosal IL-33 in active UC, localized primarily to intestinal epithelial cells (IEC) and colonic inflammatory infiltrates. Importantly, increased expression of full-length IL-33, representing the most bioactive form, was detected in UC epithelium, whereas elevated levels of cleaved IL-33 were present in IBD serum. ST2 isoforms were differentially modulated in UC epithelium, and sST2, a soluble decoy receptor with anti-inflammatory properties, was also elevated in IBD serum. Infliximab (anti-TNF) treatment of UC decreased circulating IL-33 and increased sST2, whereas stimulation of HT-29 IEC confirmed IL-33 and sST2 regulation by TNF. Similarly, IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6, and IL-17 from mucosal immune cells in SAMP mice. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis, is modulated by anti-TNF therapy, and may represent a specific biomarker for active UC.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pastorelli
authors.forename: Rekha R
authors.initials: RR
authors.lastname: Garg
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Hoang
authors.forename: Luisa
authors.initials: L
authors.lastname: Spina
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mattioli
authors.forename: Melania
authors.initials: M
authors.lastname: Scarpa
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiocchi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vecchi
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Pizarro
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000378:metabolism*; D000069285:Infliximab; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000097:blood / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D011956:Receptors, Cell Surface / Q000097:blood / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab
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