Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-04, Vol.107 (17), p.8017-8022
• Main Authors: Pastorelli, Luca, Garg, Rekha R, Hoang, Sharon B, Spina, Luisa, Mattioli, Benedetta, Scarpa, Melania, Fiocchi, Claudio, Vecchi, Maurizio, Pizarro, Theresa T
• Format: Article
• Language: English
• Subjects: Adipocytes; Animals; Antibodies, Monoclonal; Autoimmune diseases; Biological Sciences; Biomarkers; Blotting, Western; Cells; Cells, Cultured; Cytokines; Disease models; Drug therapy; Epithelial cells; Humans; Immunohistochemistry; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - metabolism; Infliximab; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukins - blood; Interleukins - metabolism; Intestinal Mucosa - metabolism; Lymph Nodes - metabolism; Messenger RNA; Mice; Mucosa; Proteins; Receptors; Receptors, Cell Surface - blood; Receptors, Cell Surface - metabolism; Rodents; T-Lymphocytes, Helper-Inducer - immunology; TNF inhibitors; Tumor Necrosis Factor-alpha - metabolism; Ulcerative colitis; Up-Regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0912678107

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.