Endothelial Surface N-Glycans Mediate Monocyte Adhesion and Are Targets for Anti-inflammatory Effects of Peroxisome Proliferator-activated Receptor γ Ligands
Endothelial Surface N-Glycans Mediate Monocyte Adhesion and Are Targets for Anti-inflammatory Effects of Peroxisome Proliferator-activated Receptor γ Ligands
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DOI：
10.1074/jbc.m111.247981
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发表时间：
2011-11-04
影响因子：
4.8
通讯作者：
Patel, Rakesh P.
中科院分区：
文献类型：
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作者：
Chacko, Balu K.;Scott, David W.;Patel, Rakesh P.
内皮-单核细胞相互作用受粘附分子调节，在血管炎性疾病的发展中起关键作用。内皮细胞中的过氧化物酶体增殖物激活受体（PPAR）γ激活被认为介导抑制单核细胞滚动和粘附的抗炎作用。在此，证据提供了一种新的机制，抗炎作用的过氧化物酶体增殖物激活受体γ配体的作用，涉及抑制促炎性丝氨酸依赖性上调内皮N-聚糖。TNF α处理人脐静脉内皮细胞增加高甘露糖/杂合N-聚糖的表面表达。这些糖在介导THP-1或初级人单核细胞滚动和粘附中的作用由竞争研究表明，其中添加α-甲基甘露糖而不是α-甲基葡萄糖在流动期间抑制单核细胞滚动和粘附，但在静态条件下不抑制。这一结果支持粘附分子为糖表位提供支架以介导与同源受体的粘附的观点。一组结构不同的PPAR γ激动剂均降低了内皮高甘露糖/杂合N-聚糖的TNF α依赖性表达。使用罗格列酮作为模型过氧化物酶体增殖物激活受体γ激动剂，降低TNF α诱导的高甘露糖N-聚糖表达，我们证明了这些碳水化合物残基在THP-1滚动和粘附中的作用，其独立于内皮表面粘附分子表达（ICAM-1和E-选择素）。来自N-聚糖加工基因阵列的数据将α-甘露聚糖酶（MAN 1A 2和MAN 1C 1）鉴定为TNF α下调的靶点，其被罗格列酮逆转，结果与改变的高甘露糖/杂合N-聚糖表位一致。总之，我们提出了一种新的抗炎机制，内皮细胞的过氧化物酶体增殖物激活受体γ激活，涉及靶向蛋白质的翻译后修饰的粘附分子，特别是N-糖基化。
Endothelial-monocyte interactions are regulated by adhesion molecules and key in the development of vascular inflammatory disease. Peroxisome proliferator-activated receptor (PPAR) gamma activation in endothelial cells is recognized to mediate anti-inflammatory effects that inhibit monocyte rolling and adhesion. Herein, evidence is provided for a novel mechanism for the anti-inflammatory effects of PPAR gamma ligand action that involves inhibition of proinflammatory cytokine-dependent up-regulation of endothelial N-glycans. TNF alpha treatment of human umbilical vein endothelial cells increased surface expression of high mannose/hybrid N-glycans. A role for these sugars in mediating THP-1 or primary human monocyte rolling and adhesion was indicated by competition studies in which addition of alpha-methylmannose, but not alpha-methylglucose, inhibited monocyte rolling and adhesion during flow, but not under static conditions. This result supports the notion that adhesion molecules provide scaffolds for sugar epitopes to mediate adhesion with cognate receptors. A panel of structurally distinct PPAR gamma agonists all decreased TNF alpha-dependent expression of endothelial high mannose/hybrid N-glycans. Using rosiglitazone as a model PPAR gamma agonist, which decreased TNF alpha-induced high mannose N-glycan expression, we demonstrate a role for these carbohydrate residues in THP-1 rolling and adhesion that is independent of endothelial surface adhesion molecule expression (ICAM-1 and E-selectin). Data from N-glycan processing gene arrays identified alpha-mannosidases (MAN1A2 and MAN1C1) as targets for down-regulation by TNF alpha, which was reversed by rosiglitazone, a result consistent with altered high mannose/hybrid N-glycan epitopes. Taken together we propose a novel anti-inflammatory mechanism of endothelial PPAR gamma activation that involves targeting protein post-translational modification of adhesion molecules, specifically N-glycosylation.