Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction
Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction
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DOI：
10.1161/01.atv.19.9.2094
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发表时间：
1999-09-01
影响因子：
8.7
通讯作者：
Demer, LL
中科院分区：
文献类型：
--
作者：
Jackson, SM;Parhami, F;Demer, LL
急性和慢性炎症以及相关疾病如动脉粥样硬化和类风湿性关节炎的早期事件是内皮细胞（EC）表面上特异性粘附分子的诱导表达，其随后结合白细胞。过氧化物酶体增殖物激活受体（PPARs）是转录因子核受体超家族的成员，由脂肪酸代谢物、过氧化物酶体增殖物和噻唑烷二酮类激活，现在被认为是炎症反应中的重要介质。PAR激活剂是否影响内皮细胞的炎症反应尚不清楚。我们发现，PPAR激活剂15-脱氧-δ（12，14）-前列腺素J（2）（15 d-PGJ（2））、Wyeth 14643、ciglitazone和troglitazone，而不是BRL 49653，部分抑制诱导的血管细胞粘附分子-1（VCAM-1）的表达，如通过ELISA测量的，以及单核细胞与由佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）或脂多糖激活的人主动脉内皮细胞（HAEC）的结合。“天然”PPAR激活剂15 d-PGJ（2）具有最大效力，并且是唯一能够部分抑制E-选择素和嗜中性粒细胞样HL 60细胞与PMA激活的HAEC结合的诱导表达的测试分子。PMA诱导的细胞内粘附分子-1不受任何测试分子的影响。通过逆转录-聚合酶链反应和核糖核酸酶保护试验，在HAEC中检测到PPAR-alpha和PPAR-gamma mRNA;然而，我们尚未确定哪些PPARs（如果有的话）介导了这一过程。这些结果表明，某些过氧化物酶体增殖物激活剂可能有助于限制慢性炎症介导的VCAM-1和单核细胞，而不影响急性炎症介导的E-选择素和中性粒细胞结合。
An early event in acute and chronic inflammation and associated diseases such as atherosclerosis and rheumatoid arthritis is the induced expression of specific adhesion molecules on the surface of endothelial cells (ECs), which subsequently bind leukocytes. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor superfamily of transcription factors, an activated by fatty acid metabolites, peroxisome proliferators, and thiazolidinediones and are now recognized as important mediators in the inflammatory response. Whether PAR activators influence the inflammatory responses of ECs is unknown. We show that the PPAR activators 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), Wyeth 14643, ciglitazone, and troglitazone, but not BRL 49653, partially inhibit the induced expression of vascular cell adhesion molecule-1 (VCAM-1), as measured by ELISA, and monocyte binding to human aortic endothelial cells (HAECs) activated by phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide. The "natural" PPAR activator 15d-PGJ(2) had the greatest potency and was the only tested molecule capable of partially inhibiting the induced expression of E-selectin and neutrophil-like HL60 cell binding to PMA-activated HAECs. Intracellular adhesion molecule-1 induction by PMA was unaffected by any of the molecules tested. Both PPAR-alpha and PPAR-gamma mRNAs were detected in HAECs by using reverse transcription-polymerase chain reaction and a ribonuclease protection assay; however, we have yet to determine which, if any, of the PPARs are mediating this process. These results suggest that certain PPAR activators may help limit chronic inflammation mediated by VCAM-1 and monocytes without affecting acute inflammation mediated by E-selectin and neutrophil binding.