Laminin receptor mediates anti-inflammatory and anti-thrombogenic effects of pigment epithelium-derived factor in myeloma cells
Laminin receptor mediates anti-inflammatory and anti-thrombogenic effects of pigment epithelium-derived factor in myeloma cells
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DOI：
10.1016/j.bbrc.2013.12.060
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发表时间：
2014-01-17
影响因子：
3.1
通讯作者：
Yamagishi, Sho-ichi
中科院分区：
文献类型：
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作者：
Matsui, Takanori;Higashimoto, Yuichiro;Yamagishi, Sho-ichi
色素上皮衍生因子（PEDF）在细胞培养和动物模型中都具有抗炎和抗血栓形成的特性。虽然脂肪甘油三酯脂肪酶（ATGL）和层粘胶蛋白受体（LR）是两种被认为是PEDF的受体，但哪种受体主要介导PEDF的有益作用在很大程度上是未知的。在这项研究中，我们解决了这个问题。转染siRNA抑制LR （siLR）和siATGL可显著降低人培养骨髓瘤细胞中LR和ATGL的水平。10 nM PEDF显著降低了sico或siatcl转染的骨髓瘤细胞中血管内皮生长因子（VEGF）、单核细胞趋化蛋白-1 （MCP-1）、细胞间细胞粘附分子-1 （ICAM-1）和纤溶酶原激活物抑制剂-1 (PAI-1) mRNA水平，而PEDF在silr转染的细胞中增加而不是降低了这些基因的表达。中和抗LR抗体（LR- ab）或与LR结合的LR拮抗剂可降低骨髓瘤细胞中VEGF、MCP-1、ICAM-1和PAI-1的mRNA水平。此外，预处理LR- ab或LR拮抗剂可抑制PEDF与LR的结合，从而阻断PEDF在骨髓瘤细胞中的作用。此外，高浓度LR激动剂模拟了PEDF对骨髓瘤细胞中这些基因表达的作用。本研究提示PEDF通过与LR的相互作用引起骨髓瘤细胞的抗血管生成、抗炎和抗血栓形成反应。LR激动剂和拮抗剂的靶域可能参与了骨髓瘤细胞pedf信号传导到基因抑制的过程。(C) 2013爱思唯尔公司版权所有。
Pigment epithelium-derived factor (PEDF) has anti-inflammatory and anti-thrombogenic properties both in cell culture and animal models. Although adipose triglyceride lipase (ATGL) and laminin receptor (LR) are two putative receptors for PEDF, which receptor mainly mediates the beneficial effects of PEDF is largely unknown. In this study, we addressed the issue. siRNA raised against LR (siLR) and siATGL transfection dramatically decreased LR and ATGL levels in human cultured myeloma cells, respectively. Ten nM PEDF significantly reduced vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) mRNA levels in siCon- or siATGL-transfected myeloma cells, whereas PEDF increased rather than decreased these gene expressions in siLR-transfected cells. Neutralizing antibody directed against LR (LR-Ab) or LR antagonist actually bound to LR and reduced mRNA levels of VEGF, MCP-1, ICAM-1 and PAI-1 in myeloma cells. Further, pre-treatment of LR-Ab or LR antagonist suppressed the binding of PEDF to LR and resultantly blocked the effects of PEDF in myeloma cells. In addition, high concentration of LR agonist mimicked the actions of PEDF on these gene expressions in myeloma cells. This study indicates that PEDF causes anti-angiogenic, anti-inflammatory and anti-thrombogenic reactions in myeloma cells through the interaction with LR. Target domain of LR agonist and antagonist might be involved in the PEDF-signaling to gene suppression in myeloma cells. (C) 2013 Elsevier Inc. All rights reserved.