Lo S K, Bovis L, Matura R, Zhu B, He S, Lum H, Turco S J, Ho J L
Department of Medicine, Cornell University Medical College, NY 10021, USA.
J Immunol. 1998 Feb 15;160(4):1857-65.
We previously identified the structural requirement for the inhibitory activity of Leishmania lipophosphoglycan (LPG) to block endothelial adhesion to monocytes. Here we showed that LPG reduces transendothelial migration of monocytes. LPG pretreatment of endothelial cells (2 microM, 1 h) reduced monocyte migration across endothelial cells activated by bacterial endotoxin (LPS) or IL-1beta (60 and 46%, respectively). A fragment of LPG (i.e., repeating phosphodisaccharide (consisting of galactosyl-mannose)) and LPG coincubated with LPG-neutralizing mAb lacks inhibitory activity on monocyte migration. Pretreatment of monocytes with LPG (2 microM, 1 h) also did not affect monocyte migration through control or LPS-activated endothelial cells. FACS analysis reveals that LPG treatment blocked the LPS-mediated expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 on endothelial cells and monocyte adhesion without altering the integrity of the endothelial monolayer. LPG (2 microM, 1 h) alone was capable of altering the expression and distribution of two junctional adhesion molecules, CD31 and vascular endothelium cadherin, as well as reversing the effects of LPS on these proteins. The induction of endothelial cells by LPS to transcribe and release monocyte chemoattractant protein-1 (MCP-1) was significantly reduced by LPG (40-65%). LPG treatment of nonactivated endothelial cells also suppressed by 55 to 75% the monocyte migration triggered by a MCP-1 chemoattractant gradient, and coincubation of LPG with neutralizing mAb abrogated the inhibitory activity. Together, these data point to a novel anti-inflammatory function of LPG in reducing monocyte migration across endothelial cells via a mechanism of inhibition of endothelial expression of cell adhesion molecules, modulation of intercellular junctional proteins, and synthesis of MCP-1.
我们之前确定了利什曼原虫脂磷壁酸（LPG）抑制活性的结构要求，该活性可阻止内皮细胞与单核细胞的黏附。在此我们表明，LPG可减少单核细胞的跨内皮迁移。用LPG预处理内皮细胞（2微摩尔/升，1小时）可减少单核细胞穿过由细菌内毒素（LPS）或IL-1β激活的内皮细胞的迁移（分别减少60%和46%）。LPG的一个片段（即重复磷酸二糖（由半乳糖基-甘露糖组成））以及与LPG中和单克隆抗体共同孵育的LPG对单核细胞迁移缺乏抑制活性。用LPG预处理单核细胞（2微摩尔/升，1小时）也不影响单核细胞通过对照或LPS激活的内皮细胞的迁移。流式细胞术分析显示，LPG处理可阻断LPS介导的内皮细胞上E-选择素、细胞间黏附分子-1和血管细胞黏附分子-1的表达以及单核细胞黏附，而不会改变内皮单层的完整性。单独的LPG（2微摩尔/升，1小时）能够改变两种连接黏附分子CD31和血管内皮钙黏蛋白的表达和分布，并逆转LPS对这些蛋白质的影响。LPG可使LPS诱导内皮细胞转录和释放单核细胞趋化蛋白-1（MCP-1）的水平显著降低（40 - 65%）。用LPG处理未激活的内皮细胞也可使由MCP-1趋化梯度触发的单核细胞迁移抑制55%至75%，并且LPG与中和单克隆抗体共同孵育可消除这种抑制活性。总之，这些数据表明LPG具有一种新的抗炎功能，即通过抑制内皮细胞黏附分子的表达、调节细胞间连接蛋白以及合成MCP-1来减少单核细胞跨内皮细胞的迁移。
