Novel role of the serine protease inhibitor elafin in gluten-related disorders.
Novel role of the serine protease inhibitor elafin in gluten-related disorders.
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DOI：
10.1038/ajg.2014.48
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发表时间：
2014-05
影响因子：
9.8
通讯作者：
Verdu, Elena F.
中科院分区：
文献类型：
--
作者：
Galipeau, Heather J.;Wiepjes, Michelle;Motta, Jean-Paul;Schulz, Jessica D.;Jury, Jennifer;Natividad, Jane M.;Pinto-Sanchez, Ines;Sinclair, Daniel;Rousset, Perrine;Martin-Rosique, Rebeca;Bermudez-Humaran, Luis;Leroux, Jean Christophe;Murray, Joseph A.;Smecuol, Edgardo;Bai, Julio C.;Vergnolle, Nathalie;Langella, Philippe;Verdu, Elena F.
内源性丝氨酸蛋白酶抑制剂Elafin调节结肠炎症。我们使用人小肠组织和麦醇溶蛋白脱酰胺体外试验研究了弹力素在乳糜泻（CD）中的作用。我们还研究了弹性蛋白酶在麸质敏感性小鼠模型中的潜在有益作用。通过免疫荧光法测定活动性CD患者、治疗CD患者和对照组（无CD）患者小肠中的上皮弹性蛋白表达。体外研究了弹力素与人组织型转氨酶-2（TG-2）的相互作用。将33-mer肽（一种高免疫原性麦胶蛋白肽）与不同浓度的TG-2和弹性蛋白酶一起孵育。通过液相色谱-质谱法分析33-mer肽的脱酰胺程度。使用重组乳酸乳球菌载体将弹性蛋白递送至谷蛋白敏感小鼠的肠道。评估小肠屏障功能、炎症、蛋白水解活性和闭合小带-1（ZO-1）表达。与对照组相比，活动性CD患者小肠上皮中的弹性蛋白表达较低。在体外，弹性蛋白酶显着减缓了33-mer肽脱酰胺的动力学，使其更具免疫原性的形式。用由L. lactis载体使炎症正常化，改善渗透性并维持ZO-1表达。活动性CD患者小肠中弹性蛋白酶表达降低，弹性蛋白酶减少33-mer肽脱酰胺作用，以及在谷蛋白敏感小鼠中观察到的屏障增强和抗炎作用，表明该分子可能在谷蛋白相关疾病中具有病理生理学和治疗重要性。
Elafin, an endogenous serine protease inhibitor, modulates colonic inflammation. We investigated the role of elafin in celiac disease (CD) using human small intestinal tissues and in vitro assays of gliadin deamidation. We also investigated potential beneficial effects of elafin in a mouse model of gluten sensitivity. Epithelial elafin expression in the small intestine of patients with active CD, treated CD and controls without CD was determined by immunofluorescence. Interaction of elafin with human tissue transglutaminase-2 (TG-2) was investigated in vitro. The 33-mer peptide, a highly immunogenic gliadin peptide, was incubated with TG-2 and elafin at different concentrations. The degree of deamidation of the 33-mer peptide was analyzed by liquid chromatography-mass spectrometry. Elafin was delivered to the intestine of gluten-sensitive mice using a recombinant Lactococcus lactis vector. Small intestinal barrier function, inflammation, proteolytic activity, and zonula occludens-1 (ZO-1) expression were assessed. Elafin expression in the small intestinal epithelium was lower in patients with active CD compared to control patients. In vitro, elafin significantly slowed the kinetics of the deamidation of the 33-mer peptide to its more immunogenic form. Treatment of gluten-sensitive mice with elafin delivered by the L. lactis vector normalized inflammation, improved permeability and maintained ZO-1 expression. The decreased elafin expression in small intestine of patients with active CD, the reduction of 33-mer peptide deamidation by elafin, coupled to the barrier enhancing and anti-inflammatory effects observed in gluten sensitive mice, suggest this molecule may have pathophysiological and therapeutic importance in gluten-related disorders.
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影响因子：
17.1
作者：
Motta, Jean-Paul;Bermudez-Humaran, Luis G.;Vergnolle, Nathalie
通讯作者：
Vergnolle, Nathalie
影响因子：
2.9
作者：
Guyot, N;Zani, ML;Moreau, T
通讯作者：
Moreau, T
影响因子：
9.8
作者：
Biesiekierski, Jessica R.;Newnham, Evan D.;Gibson, Peter R.
通讯作者：
Gibson, Peter R.
影响因子：
15.9
作者：
Marietta, E;Black, K;Murray, JA
通讯作者：
Murray, JA
影响因子：
5.5
作者：
Schmid, Michael;Fellermann, Klaus;Wehkamp, Jan
通讯作者：
Wehkamp, Jan