Thrombospondin-1 up-regulates expression of cell adhesion molecules and promotes monocyte binding to endothelium
Thrombospondin-1 up-regulates expression of cell adhesion molecules and promotes monocyte binding to endothelium
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DOI：
10.1096/fj.04-3310fje
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发表时间：
2005-04-01
期刊：
影响因子：
4.8
通讯作者：
Byzova, TV
中科院分区：
文献类型：
--
作者：
Narizhneva, NV;Razorenova, OV;Byzova, TV
负责白细胞-内皮相互作用的细胞粘附分子（CAM）的表达在炎症和动脉粥样硬化中起着至关重要的作用。上调血管CAM-1 （VCAM-1）、细胞内CAM-1 （ICAM-1）和e -选择素的表达可促进单核细胞向损伤部位募集，被认为是动脉粥样硬化斑块形成的关键步骤。引发这种最初反应的因素还没有得到很好的理解。由于血小板活化不仅促进血栓形成，而且还促进动脉粥样硬化的早期阶段，我们考虑了血小板反应蛋白-1 （TSP-1）的作用，TSP-1是一种从活化的血小板中大量释放并积聚在血管损伤部位的基质细胞蛋白，可以调节CAM的表达。TSP-1诱导各种来源内皮细胞表达VCAM-1和ICAM-1，从而导致单核细胞附着显著增加。这种效应可以通过一种从TSP-1的c端结构域衍生的肽来模拟，这种肽已知可以与细胞表面的CD47相互作用。通过抑制抗体和小干扰RNA敲除CD47，进一步证明了CD47在细胞对TSP-1反应中的重要作用。此外，我们证明内源性TSP-1的分泌及其与细胞表面CD47的相互作用介导了内皮细胞对主要促炎剂肿瘤坏死因子α (tnf - α)的反应。综上所述，本研究确定了一种调节CAM表达和随后单核细胞与内皮结合的新机制，这可能影响抗动脉粥样硬化治疗策略的发展。
Expression of cell adhesion molecules (CAM) responsible for leukocyte-endothelium interactions plays a crucial role in inflammation and atherogenesis. Up-regulation of vascular CAM-1 (VCAM-1), intracellular CAM-1 (ICAM-1), and E-selectin expression promotes monocyte recruitment to sites of injury and is considered to be a critical step in atherosclerotic plaque development. Factors that trigger this initial response are not well understood. As platelet activation not only promotes thrombosis but also early stages of atherogenesis, we considered the role of thrombospondin-1 (TSP-1), a matricellular protein released in abundance from activated platelets and accumulated in sites of vascular injury, as a regulator of CAM expression. TSP-1 induced expression of VCAM-1 and ICAM-1 on endothelium of various origins, which in turn, resulted in a significant increase of monocyte attachment. This effect could be mimicked by a peptide derived from the C-terminal domain of TSP-1 and known to interact with CD47 on the cell surface. The essential role of CD47 in the cellular responses to TSP-1 was demonstrated further using inhibitory antibodies and knockdown of CD47 with small interfering RNA. Furthermore, we demonstrated that secretion of endogenous TSP-1 and its interaction with CD47 on the cell surface mediates endothelial response to the major proinflammatory agent, tumor necrosis factor alpha (TNF-alpha). Taken together, this study identifies a novel mechanism regulating CAM expression and subsequent monocyte binding to endothelium, which might influence the development of anti-atherosclerosis therapeutic strategies.