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Title: Genetic Deletion of Tissue Inhibitor of Metalloproteinase-1/TIMP-1 Alters Inflammation and Attenuates Fibrosis in Dextran Sodium Sulphate-induced Murine Models of Colitis
Authors: Breynaert, Christine
de Bruyn, Magali
ARIJS, Ingrid 
Cremer, Jonathan
Martens, Erik
Van Lommel, Leentje
Geboes, Karel
De Hertogh, Gert
Schuit, Frans
Ferrante, Marc
Vermeire, Severine
Ceuppens, Jan
Opdenakker, Ghislain
Van Assche, Gert
Issue Date: 2016
Source: JOURNAL OF CROHNS & COLITIS, 10(11), p. 1336-1350
Abstract: Increased levels of tissue inhibitor of metalloproteinase-1 [TIMP-1] have been detected in both inflammatory and fibrotic lesions in Crohn's disease. In a murine model of chronic inflammation, fibrosis was associated with an increase in TIMP-1 and inhibition of matrix metalloproteinase [MMP]-mediated degradation. We investigated the effect of TIMP-1 deficiency in acute and chronic murine models of colitis. Colitis was induced via oral administration of dextran sodium sulphate [DSS] to B6.129S4-Timp1(tm1Pds)/J knock-out [KO] and C57BL/6J wild-type [WT] mice. Levels of inflammation and fibrosis were assessed and gelatin zymographies and gene expression microarrays were performed. Compared with WT mice, TIMP-1 KO mice had higher inflammatory parameters after acute DSS administration and developed less fibrosis after chronic DSS administration. MMP-2 levels were increased in WT versus TIMP-1 KO mice with acute colitis, whereas a trend for higher proMMP-9 levels was observed in WT versus TIMP-1 KO mice with chronic colitis. In control conditions, several immune-related genes [e.g Ido1, Cldn8] were differentially expressed between young TIMP-1 KO and WT mice, but to a lesser extent between older TIMP-1 KO and WT mice. In response to DSS, the gene expression pattern was significantly different between young TIMP-1 KO and WT mice, whereas it was similar in older TIMP-1 KO and WT mice. TIMP-1 deficiency leads to differential expression of immune-related genes and to attenuated development of fibrosis. Unravelling the role of TIMP-1 in intestinal remodelling is necessary to develop more effective and more targeted therapeutic strategies for intestinal fibrosis.
Notes: [Breynaert, Christine; de Bruyn, Magali; Arijs, Ingrid; Cremer, Jonathan; Ferrante, Marc; Vermeire, Severine; Van Assche, Gert] Katholieke Univ Leuven, Dept Clin & Expt Med, Translat Res Ctr Gastrointestinal Disorders TARGI, Leuven, Belgium. [Breynaert, Christine; Cremer, Jonathan; Ceuppens, Jan] Katholieke Univ Leuven, Dept Microbiol & Immunol, Lab Clin Immunol, Leuven, Belgium. [de Bruyn, Magali; Martens, Erik; Opdenakker, Ghislain] Katholieke Univ Leuven, Dept Microbiol & Immunol, Lab Immunobiol, Leuven, Belgium. [Arijs, Ingrid] Hasselt Univ, Fac Med & Life Sci, Hasselt, Belgium. [Van Lommel, Leentje; Schuit, Frans] Katholieke Univ Leuven, Gene Express Unit, Dept Cellular & Mol Med, Leuven, Belgium. [De Hertogh, Gert] Katholieke Univ Leuven, Dept Imaging & Pathol, Translat Cell & Tissue Res, Leuven, Belgium. [Ferrante, Marc; Vermeire, Severine; Van Assche, Gert] Katholieke Univ Leuven, Univ Hosp Leuven, Dept Gastroenterol & Hepatol, Leuven, Belgium.
Keywords: Colitis; DSS; fibrosis; TIMP-1; IBD;colitis; DSS; fibrosis; TIMP-1; IBD
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ISSN: 1873-9946
e-ISSN: 1876-4479
DOI: 10.1093/ecco-jcc/jjw101
ISI #: 000387990000012
Rights: Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email:
Category: A1
Type: Journal Contribution
Validations: ecoom 2017
Appears in Collections:Research publications

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