Background: Matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), a disintegrin and metalloprotease with thrombospondin motifs [ADAM(TS)s] and growth factors are involved in inflammation and tissue damage and repair, all occurring in inflammatory bowel disease (IBD). We studied the impact of anti-inflammatory therapy with infliximab on mucosal expression of these tissue remodeling genes in patients with IBD.
Methods: Mucosal gene expression of 23 MMPs, 4 TIMPs, 50 ADAM(TS)s, and 158 growth factors was investigated in 61 patients with IBD before and after the first infliximab therapy and in 12 controls, with microarrays and quantitative RT-PCR. Protein localization, mucosal gelatinase levels, and net gelatinolytic activity were investigated by immunohistochemistry, zymography analysis, and gelatin degradation assay, respectively.
Results: In patients with active IBD before infliximab versus controls, gene expression of many MMPs, TIMPs, ADAM(TS)s, and growth factors was upregulated, whereas colonic expression of MMP28 and TGFA and ileal expression of ADAMDEC1 and AGT were downregulated. After controlling inflammation with infliximab, most gene dysregulations observed at baseline were restored in responders. Increased ratio of MMP1/TIMP1 expression at baseline in active IBD was restored in responders with colonic mucosal healing. With immunohistochemistry, protein localization differences of MMP1, MMP3, REG1A, and TIMP1 were shown between active IBD and control mucosa. With zymography analysis and gelatin degradation assay, higher gelatinase levels and net gelatinolytic activity were measured before infliximab and levels normalized after infliximab.
Conclusions: Our data suggest that suppression of inflammation results in the arrest of epithelial damage and subsequent mucosal healing. Therefore, the therapeutic potential of agents targeting MMPs or growth factors as primary therapy seems rather complex.
Article first published online 27 December 2013
*Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine;
†Laboratory of Immunobiology (Rega Institute for Medical Research), Department of Microbiology and Immunology;
‡Translational Cell and Tissue Research, Department of Imaging and Pathology;
§Gene Expression Unit, Department of Cellular and Molecular Medicine; and
‖Leuven Food Science and Nutrition Research Centre (LFoRCe), KULeuven, Leuven, Belgium.
Reprints: Ingrid Arijs, PhD, Translational Research Center for Gastrointestinal Disorders (TARGID), KULeuven, University of Hospital Gasthuisberg, Herestraat 49, Mailbox 7003, B-3000 Leuven, Belgium (e-mail: firstname.lastname@example.org).
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Supported by grants from the Fund for Scientific Research-Flanders (FWO-Flanders), Belgium (FWO project nr.G.0440.06 and nr.G.0479.10). I. Arijs is a postdoctoral fellow and S. Vermeire is a clinical researcher of FWO-Flanders. M. de Bruyn and C. Breynaert are supported by a grant of the Agency for Innovation by Science and Technology in Flanders (IWT).
P. Rutgeerts, S. Vermeire, M. Ferrante, G. Van Assche, and G. De Hertogh report following conflicts of interest: grant support, lecture fees, and consulting fees from Centocor and Schering-Plough. The remaining authors have no conflicts of interest to disclose.
Received October 08, 2013
Accepted November 9, 2013