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Inflammatory Bowel Disease-Associated Interleukin-33 Is Preferentially Expressed in Ulceration-Associated Myofibroblasts

https://doi.org/10.2353/ajpath.2010.100378Get rights and content
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Interleukin-33 (IL-33) is a novel member of the interleukin-1 family that induces mucosal pathology in vivo and may drive fibrosis development and angiogenesis. To address its potential role in inflammatory bowel disease, we explored its tissue expression in biopsy specimens from untreated ulcerative colitis patients, observing a 2.6-fold up-regulation of IL-33 mRNA levels, compared to controls. Immunohistochemical analyses of surgical specimens showed that a prominent source of IL-33 in ulcerative colitis lesions were ulceration-associated myofibroblasts that co-expressed the fibroblast marker heat shock protein 47, platelet-derived growth factor receptor (PDGFR)β, and, in part, the myofibroblast marker α-smooth muscle actin (SMA). In contrast, IL-33-positive myofibroblasts were almost absent near the deep fissures seen in Crohn's disease. A screen of known and putative activators of IL-33 in cultured fibroblasts revealed that the Toll-like receptor-3 agonist poly (I:C) was among the strongest inducers of IL-33 and that it synergized with transforming growth factor-β, a combination also known to boost myofibroblast differentiation. Experimental wound healing in rat skin revealed that the de novo induction of IL-33 in pericytes and the possible activation of scattered, tissue-resident IL-33+PDGFRβ+αSMA fibroblast-like cells were early events that preceded the later appearance of IL-33+PDGFRβ+αSMA+ cells. In conclusion, our data point to a novel role for IL-33 in mucosal healing and wound repair and to an interesting difference between ulcerative colitis and Crohn's disease.

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Supported by Helse Sør-Øst (2008139 and 2007044), the Norwegian Cancer Society (PK01-2006-0448 and PK01-2007-0199), the Research Council of Norway (133924/300), and the University of Oslo (131406). J.S. and A.M.K. are Ph.D. and Postdoctoral Fellows of Helse Sør-Øst, J.P. and J.B. are Postdoctoral Fellows of the Norwegian Cancer Society.

J.P. and T.O. contributed equally.

Disclosure: G.H. is inventor of patent WO 2004/056868 A2.

Current address for J.P.: Dept. of Obstetrics and Fetal-Maternal Medicine, Medical University of Vienna, Austria.