英夫利昔单抗可恢复炎症性肠病患者功能失调的基质重塑蛋白和生长因子基因表达。
Infliximab restores the dysfunctional matrix remodeling protein and growth factor gene expression in patients with inflammatory bowel disease.
作者信息
de Bruyn Magali, Machiels Kathleen, Vandooren Jennifer, Lemmens Bart, Van Lommel Leentje, Breynaert Christine, Van der Goten Jan, Staelens Dominiek, Billiet Thomas, De Hertogh Gert, Ferrante Marc, Van Assche Gert, Vermeire Séverine, Opdenakker Ghislain, Schuit Frans, Rutgeerts Paul, Arijs Ingrid
机构信息
*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.
出版信息
Inflamm Bowel Dis. 2014 Feb;20(2):339-52. doi: 10.1097/01.MIB.0000438430.15553.90.
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.
背景
基质金属蛋白酶（MMPs）、金属蛋白酶组织抑制剂（TIMPs）、含血小板反应蛋白基序的解聚素和金属蛋白酶[ADAM(TS)s]以及生长因子参与炎症、组织损伤和修复过程，这些过程均发生在炎症性肠病（IBD）中。我们研究了英夫利昔单抗抗炎治疗对IBD患者这些组织重塑基因黏膜表达的影响。
方法
采用微阵列和定量逆转录聚合酶链反应，对61例IBD患者在首次英夫利昔单抗治疗前后以及12例对照者的23种MMPs、4种TIMPs、50种ADAM(TS)s和158种生长因子的黏膜基因表达进行了研究。分别通过免疫组织化学、酶谱分析和明胶降解试验研究蛋白定位、黏膜明胶酶水平和净明胶溶解活性。
结果
与对照组相比，英夫利昔单抗治疗前活动期IBD患者中许多MMPs、TIMPs、ADAM(TS)s和生长因子的基因表达上调，而MMP28和TGFA的结肠表达以及ADAMDEC1和AGT的回肠表达下调。英夫利昔单抗控制炎症后，反应者中大多数在基线时观察到的基因失调得以恢复。结肠黏膜愈合的反应者中，活动期IBD基线时升高的MMP1/TIMP1表达比值恢复正常。通过免疫组织化学显示，活动期IBD和对照黏膜之间存在MMP1、MMP3、REG1A和TIMP1的蛋白定位差异。通过酶谱分析和明胶降解试验，英夫利昔单抗治疗前测得较高的明胶酶水平和净明胶溶解活性，英夫利昔单抗治疗后水平恢复正常。
结论
我们的数据表明，炎症的抑制导致上皮损伤停止并随后黏膜愈合。因此，以MMPs或生长因子为主要治疗靶点的药物的治疗潜力似乎相当复杂。
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