iNOS expression in human intestinal microvascular endothelial cells inhibits leukocyte adhesion
iNOS expression in human intestinal microvascular endothelial cells inhibits leukocyte adhesion
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DOI：
10.1152/ajpgi.1998.275.3.g592
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发表时间：
1998-09-01
影响因子：
4.5
通讯作者：
Wilson, KT
中科院分区：
文献类型：
--
作者：
Binion, DG;Fu, SD;Wilson, KT
诱导型一氧化氮合酶（iNOS）产生一氧化氮（NO）的增加与肠道炎症有关，包括人类炎症性肠病。然而，NO可以下调内皮细胞的激活和白细胞粘附，这是炎症反应的关键步骤。利用人肠道微血管内皮细胞（HIMEC）的原代培养，我们确定了NO在调节HIMEC激活和与白细胞相互作用中的作用。非选择性（ng -单甲基-l -精氨酸）和特异性（n -亚氨基乙基-l -赖氨酸）竞争性iNOS抑制剂均显著增加细胞因子和脂多糖激活的HIMEC与白细胞的结合。NOS底物l -精氨酸的粘附增强是可逆的，在人脐静脉内皮细胞（HUVEC）中未观察到。激活HIMEC显著上调HIMEC iNOS的表达和NO的产生。在活化的HIMEC中，NOS抑制剂不会增加细胞粘附分子水平，但会导致细胞内活性氧的持续增加。此外，抗氧化化合物逆转了NOS抑制剂对himec -白细胞相互作用的影响。综上所述，这些数据表明，在HIMEC激活后，inos衍生的NO是一种内源性抗氧化剂，可下调白细胞结合并可能下调肠道炎症。诱导型一氧化氮合酶（iNOS）产生一氧化氮（NO）的增加与肠道炎症有关，包括人类炎症性肠病。然而，NO可以下调内皮细胞的激活和白细胞粘附，这是炎症反应的关键步骤。利用人肠道微血管内皮细胞（HIMEC）的原代培养，我们确定了NO在调节HIMEC激活和与白细胞相互作用中的作用。非选择性（n - g -单甲基-l -精氨酸）和特异性（n -亚氨基乙基-l -赖氨酸）竞争性iNOS抑制剂均显著增加细胞因子和脂多糖激活的HIMEC与白细胞的结合。NOS底物l -精氨酸的粘附增强是可逆的，在人脐静脉内皮细胞（HUVEC）中未观察到。激活HIMEC显著上调HIMEC iNOS的表达和NO的产生。在活化的HIMEC中，NOS抑制剂不会增加细胞粘附分子水平，但会导致细胞内活性氧的持续增加。此外，抗氧化化合物逆转了NOS抑制剂对himec -白细胞相互作用的影响。综上所述，这些数据表明，在HIMEC激活后，inos衍生的NO是一种内源性抗氧化剂，可下调白细胞结合并可能下调肠道炎症。
Increased nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) has been associated with intestinal inflammation, including human inflammatory bowel disease. However, NO can downregulate endothelial activation and leukocyte adhesion, critical steps in the inflammatory response, Using primary cultures of human intestinal microvascular endothelial cells (HIMEC), we determined the role of NO in the regulation of HIMEC activation and interaction with leukocytes. Both nonselective (NG-monomethyl-L-arginine) and specific (N-iminoethyl-L-lysine) competitive inhibitors of iNOS significantly increased binding of leukocytes by HIMEC activated with cytokines and lipopolysaccharide. Increased adhesion was reversible with the NOS substrate L-arginine and was not observed in human umbilical vein endothelial cells (HUVEC). Activation of HIMEC significantly upregulated HIMEC iNOS expression and NO production. NOS inhibitors did not augment cell adhesion molecule levels in activated HIMEC but did result in sustained increases in intracellular reactive oxygen species. In addition, antioxidant compounds reversed the effect of NOS inhibitors on HIMEC-leukocyte interaction. Taken together, these data suggest that after HIMEC activation, iNOS-derived NO is an endogenous antioxidant, downregulating leukocyte binding and potentially downregulating intestinal inflammation.Increased nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) has been associated with intestinal inflammation, including human inflammatory bowel disease. However, NO can downregulate endothelial activation and leukocyte adhesion, critical steps in the inflammatory response, Using primary cultures of human intestinal microvascular endothelial cells (HIMEC), we determined the role of NO in the regulation of HIMEC activation and interaction with leukocytes. Both nonselective (N-G-monomethyl-L-arginine) and specific (N-iminoethyl-L-lysine) competitive inhibitors of iNOS significantly increased binding of leukocytes by HIMEC activated with cytokines and lipopolysaccharide. Increased adhesion was reversible with the NOS substrate L-arginine and was not observed in human umbilical vein endothelial cells (HUVEC). Activation of HIMEC significantly upregulated HIMEC iNOS expression and NO production. NOS inhibitors did not augment cell adhesion molecule levels in activated HIMEC but did result in sustained increases in intracellular reactive oxygen species. In addition, antioxidant compounds reversed the effect of NOS inhibitors on HIMEC-leukocyte interaction. Taken together, these data suggest that after HIMEC activation, iNOS-derived NO is an endogenous antioxidant, downregulating leukocyte binding and potentially downregulating intestinal inflammation.