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Infliximab restores the dysfunctional matrix remodeling protein and growth factor gene expression in patients with
Magali de Bruyn1, Kathleen Machiels, Jennifer Vandooren
1*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.
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.
Insights
Infliximab therapy for inflammatory bowel disease (IBD) normalized tissue remodeling genes, reducing inflammation and promoting mucosal healing. This suggests complex therapeutic potential for agents targeting matrix metalloproteinases (MMPs) or growth factors.
Area of Science:
- Gastroenterology
- Molecular Biology
- Immunology
Background:
- Inflammatory bowel disease (IBD) involves complex tissue remodeling influenced by matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), ADAM(TS)s, and growth factors.
- These factors play roles in inflammation, tissue damage, and repair processes characteristic of IBD.
Purpose of the Study:
- To investigate the impact of anti-inflammatory therapy with infliximab on the mucosal expression of tissue remodeling genes in IBD patients.
- To assess changes in MMPs, TIMPs, ADAM(TS)s, and growth factors following infliximab treatment.
Main Methods:
- Gene expression analysis using microarrays and quantitative RT-PCR in 61 IBD patients before and after infliximab therapy, compared to 12 controls.
- Protein localization, gelatinase levels, and activity assessed via immunohistochemistry, zymography, and degradation assays.
Main Results:
- Active IBD showed upregulated MMPs, TIMPs, ADAM(TS)s, and growth factors compared to controls; some genes were downregulated.
- Infliximab responders exhibited restoration of most baseline gene dysregulations, alongside normalization of MMP1/TIMP1 ratio and mucosal healing.
- Elevated gelatinase levels and activity in active IBD decreased to normal levels post-infliximab treatment.
Conclusions:
- Suppression of inflammation by infliximab arrests epithelial damage and promotes mucosal healing in IBD.
- The therapeutic targeting of MMPs or growth factors as a primary strategy in IBD warrants careful consideration due to complexity.
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