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PMID: 20385815 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 107 ·No. 17 ·2010-04-27 ·Pages 8017-22

Pastorelli L, Garg RR, Hoang SB, Spina L, Mattioli B, Scarpa M, Fiocchi C, Vecchi M, Pizarro TT

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.

MeSH Terms
Animals Antibodies, Monoclonal Blotting, Western Cells, Cultured Humans Immunohistochemistry Inflammatory Bowel Diseases/immunology,metabolism Infliximab Interleukin-1 Receptor-Like 1 Protein Interleukin-33 Interleukins/blood,metabolism Intestinal Mucosa/metabolism Lymph Nodes/metabolism Mice Receptors, Cell Surface/blood,metabolism T-Lymphocytes, Helper-Inducer/immunology Tumor Necrosis Factor-alpha/metabolism Up-Regulation
Chemicals
Antibodies, Monoclonal IL1RL1 protein, human IL33 protein, human Interleukin-1 Receptor-Like 1 Protein Interleukin-33 Interleukins Receptors, Cell Surface Tumor Necrosis Factor-alpha Infliximab
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Pastorelli Luca
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Garg Rekha R
Hoang Sharon B
Spina Luisa
Mattioli Benedetta
Scarpa Melania
Fiocchi Claudio
Vecchi Maurizio
Pizarro Theresa T
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0912678107
Published
2010-04-27
Epub
2010-00-12
Pages
8017-22
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2867895
Subset
IM
Grants
NIDDK NIH HHS · DK056762 · United States
NIDDK NIH HHS · P30 DK067629 · United States
NIDDK NIH HHS · R01 DK056762 · United States
NIDDK NIH HHS · DK067629 · United States
NIDDK NIH HHS · P01 DK057880 · United States
NIDDK NIH HHS · DK057880/PPG5 · United States
External Links
PubMed source DOI: 10.1073/pnas.0912678107 PMC Full Text View journal details
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