Enhancement of CCL15 Expression and Monocyte Adhesion to Endothelial Cells (ECs) after Hypoxia/Reoxygenation and Induction of ICAM-1 Expression by CCL15 via the JAK2/STAT3 Pathway in ECs
Enhancement of CCL15 Expression and Monocyte Adhesion to Endothelial Cells (ECs) after Hypoxia/Reoxygenation and Induction of ICAM-1 Expression by CCL15 via the JAK2/STAT3 Pathway in ECs
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DOI：
10.4049/jimmunol.1202284
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发表时间：
2013-06-15
影响因子：
4.4
通讯作者：
Kim, Jiyoung
中科院分区：
文献类型：
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作者：
Park, Keun Hyung;Lee, Tae Hoon;Kim, Jiyoung
CCL 15是CC趋化因子家族的成员，是白细胞和内皮细胞（EC）的有效化学引诱物。鉴于趋化因子在血管炎症中起关键作用，我们研究了缺氧/复氧（H/R）对人CCL 15表达的影响以及CCL 15在EC中上调ICAM-1的作用。我们发现，暴露于H/R的EC增加CCL 15和ICAM-1的表达，这导致单核细胞粘附性增加的EC。进一步的研究表明，CCL 15或CCR 1的敲低减弱了H/R后EC中ICAM-1的表达，表明ICAM-1的表达被CCL 15上调。用CCL 15刺激EC显著增加ICAM-1的表达，主要通过CCR 1受体。我们观察到JAK 2和STAT 3的磷酸化被CCL 15处理的EC刺激。报告基因和染色质免疫沉淀分析的结果显示，CCL 15激活IFN-γ激活位点启动子的转录，并刺激STAT 3与ICAM-1启动子的结合。我们的数据还表明，在静态和剪切应力条件下，CCL 15增加人单核细胞与EC的细胞粘附。用JAK、PI 3 K和AKT的抑制剂预处理这些细胞阻止了CCL 15诱导的ICAM-1表达和单核细胞与EC的粘附，表明这些信号分子参与了CCL 15对ICAM-1基因的激活。结果表明，CCR 1及其配体可能是治疗炎症性疾病的潜在靶点，涉及细胞粘附分子的上调。
CCL15, a member of the CC chemokine family, is a potent chemoattractant for leukocytes and endothelial cells (ECs). Given that chemokines play key roles in vascular inflammation, we investigated the effects of hypoxia/reoxygenation (H/R) on expression of human CCL15 and a role of CCL15 in upregulating ICAM-1 in ECs. We found that exposure of ECs to H/R increased expression of CCL15 and ICAM-1, which resulted in an increase in monocyte adhesivity to the ECs. Further studies revealed that knockdown of CCL15 or CCR1 attenuated expression of ICAM-1 in ECs after H/R, suggesting that expression of ICAM-1 is upregulated by CCL15. Stimulation of ECs with CCL15 significantly increased expression of ICAM-1 predominantly via the CCR1 receptor. We observed that phosphorylation of JAK2 and STAT3 was stimulated by CCL15 treatment of ECs. Results from reporter and chromatin immunoprecipitation assays revealed that CCL15 activates transcription from the IFN-gamma activation site promoter and stimulates binding of STAT3 to the ICAM-1 promoter. Our data also showed that CCL15 increased cell adhesion of human monocytes to ECs under static and shear-stress conditions. Pretreatment of these cells with inhibitors for JAK, PI3K, and AKT prevented the CCL15-induced expression of ICAM-1 and monocyte adhesion to ECs, suggesting the involvement of those signaling molecules in ICAM-1 gene activation by CCL15. The results suggest that CCR1 and its ligands may be a potential target for treating inflammatory diseases involving upregulation of cell adhesion molecules.