Homocysteine triggers mucosal microvascular activation in inflammatory bowel disease
Homocysteine triggers mucosal microvascular activation in inflammatory bowel disease
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DOI：
10.1111/j.1572-0241.2005.41469.x
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发表时间：
2005-04-01
影响因子：
9.8
通讯作者：
Gasbarrini, A
中科院分区：
文献类型：
--
作者：
Danese, S;Sgambato, A;Gasbarrini, A
目的：同型半胱氨酸的增加有助于一些慢性炎症性疾病的病理生理。同型半胱氨酸是否参与炎症性肠病（IBD）的黏膜炎症反应尚不清楚。我们的目的是研究血浆和粘膜同型半胱氨酸在IBD患者的水平，并评估是否同型半胱氨酸可以引发炎症反应的人肠微血管内皮细胞（HIMECs.Methods）：同型半胱氨酸测定血浆，粘膜活检，固有层单核细胞（LPMC）上清液正常和IBD科目。在高半胱氨酸、TNF-α或叶酸单独或组合存在下培养HIMEC。流式细胞术检测血管细胞粘附分子1（VCAM-1）和细胞间粘附分子1（ICAM-1）的表达，ELISA检测单核细胞趋化蛋白1（MCP-1）的产生。在HIMEC提取物中通过免疫印迹评估p38和p42/44的磷酸化。T细胞和单核细胞-HIMEC粘附试验被用来评估同型半胱氨酸对白细胞粘附肠内皮细胞的影响。结果：IBD患者显示血浆和粘膜同型半胱氨酸水平显着高于对照组。IBD衍生的LPMC比对照衍生的LPMC释放更高的同型半胱氨酸。用高半胱氨酸处理HIMEC，并与TNF-α和高半胱氨酸的组合协同作用，触发HIMEC炎症，导致VCAM-1上调，MCP-1产生和p38磷酸化。这些事件导致HIMEC粘附T-和单核细胞的能力增加，并被阻断叶酸treatment.Conclusions：同型半胱氨酸是增加在粘膜和血浆中的克罗恩病和溃疡性结肠炎患者，并有助于炎症状态的粘膜IBD内皮。因此，同型半胱氨酸可能在IBD中发挥促炎作用，叶酸补充剂可以有效地靶向炎症。
Objectives: Increased homocysteine contributes to the pathophysiology of several chronic inflammatory diseases. Whether homocysteine could participate in mucosal inflammation in inflammatory bowel disease (IBD) has not been explored yet. Our aims were to study the levels of plasma and mucosal homocysteine in IBD patients and to assess whether homocysteine can trigger an inflammatory reaction on human intestinal microvascular endothelial cells (HIMECs).Methods: Homocysteine was measured in the plasma, mucosal biopsy, and lamina propria mononuclear cell (LPMC) supernatants from normal and IBD subjects. HIMEC were cultured in presence of homocysteine, TNF-alpha or folic acid, alone or in combination. Expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular cell adhesion molecule 1 was measured by flow cytometry and monocyte chemoattractant protein-1 (MCP-1) production by ELISA. Phosphorylation of p38 and p42/44 was assessed by immunoblot in HIMEC extracts. T-cell- and monocyte-HIMEC adhesion assays were used to evaluate the impact of homocysteine on leukocyte adhesion to intestinal endothelial cells.Results: Patients with IBD displayed significantly higher homocysteine plasma and mucosal levels than control subjects. IBD-derived LPMC released higher homocysteine than control-derived LPMC. Treatment of HIMEC with homocysteine, and synergistically with the combination of TNF-alpha and homocysteine, triggered HIMEC inflammation, resulting in VCAM-1 up-regulation, MCP-1 production, and p38 phosphorylation. These events lead to an increased capacity of HIMEC to adhere T- and monocyte cells and were blocked by folic acid treatment.Conclusions: Homocysteine is increased in both the mucosa and plasma of patients with Crohn's disease and ulcerative colitis and contributes to the inflammatory state of the mucosal IBD endothelium. Therefore, homocysteine could play a proinflammatory role in IBD, which can be efficiently targeted by folic acid supplementation.