Infliximab restores the dysfunctional matrix remodeling protein and growth factor gene expression in patients with inflammatory bowel disease
| Autor: | Jan Van der Goten, Jennifer Vandooren, Ingrid Arijs, Magali de Bruyn, Christine Breynaert, Gert De Hertogh, Kathleen Machiels, Paul Rutgeerts, Severine Vermeire, Bart Lemmens, Gert Van Assche, Leentje Van Lommel, Ghislain Opdenakker, Thomas Billiet, Frans Schuit, Marc Ferrante, Dominiek Staelens |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male MMP3 TGF alpha MMP1 Biopsy Inflammation Matrix metalloproteinase Real-Time Polymerase Chain Reaction Young Adult medicine Humans Immunology and Allergy Gelatinase Zymography Prospective Studies Intestinal Mucosa Aged TIMP1 Dose-Response Relationship Drug Tumor Necrosis Factor-alpha business.industry Anti-Inflammatory Agents Non-Steroidal Gastroenterology Antibodies Monoclonal Middle Aged Inflammatory Bowel Diseases Immunohistochemistry Infliximab Matrix Metalloproteinases digestive system diseases Treatment Outcome Gene Expression Regulation Immunology Intercellular Signaling Peptides and Proteins RNA Female medicine.symptom business |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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