以CRSBP-1接合子調控巨噬細胞的移動及吞噬; Regulation of Macrophage Migration and Phagocytosis by CRSBP-1 Ligands

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Title:	以CRSBP-1接合子調控巨噬細胞的移動及吞噬;Regulation of Macrophage Migration and Phagocytosis by CRSBP-1 Ligands
Authors:	蔡承遠;Cheng-yuan Tsai
Contributors:	系統生物與生物資訊研究所
Keywords:	吞噬;巨噬細胞;移動;Phogocytic uptake;Boyden chamber;Phagocytosis;Migration;Macrophage;RAW 264.7;bone marrow–derived macrophage;LYVE-1;CRSBP-1;Scratch
Date:	2010-07-20
Issue Date:	2010-12-08 14:21:44 (UTC+8)
Publisher:	國立中央大學
Abstract:	CRSBP-1 是一種存在於細胞膜的受器。當生長因子（如：血小板生長因子-BB 型及血管生長因子-A 型）由培養的細胞株合成並分泌時，可被此蛋白調控固定於細胞表面。目前並不清楚CRSBP-1 的生理功能。在我們之前的研究，發現同時剔除CRSBP-1 與Apo E 基因的老鼠比只剔除Apo E 基因的老鼠，罹患動脈血管硬化疾病的機率為低，這個發現使我們懷疑CRSBP-1 在動脈血管硬化疾病上或許扮演重要的角色。已知巨噬細胞參與動脈血管硬化疾病的病理過程，且最近被發現巨噬細胞可以表現CRSBP-1，於是我們假設CRSBP-1 和其接合子在動脈血管硬化疾病形成過程中，調控巨噬細胞移動及吞噬功能。在此實驗，我們利用CRSBP-1 的接合子，包括血小板生長因子-BB 型及另外兩個特別的接合子（血小板生長因子-胜肽及血管生長因子-胜肽，專一地結合CRSBP-1，與血小板生長因子-BB 型及血管生長因子-A 型的接受器沒有交互作用），刺激RAW 264.7 類似巨噬細胞株及骨髓衍生巨噬細胞的移動及吞噬能力，然後分別以傷口癒合試驗、Boyden chamber 試驗及吞噬FITC-葡聚醣試驗測定，得出分別在5 和40 ng/mL、10 和20 uM 及10 μg/mL為最適合濃度，且血管生長因子-胜肽出比血小板生長因子-BB 型及血小板生長因子-胜肽有更好的效果，而這種效果可以被酪氨酸激酶抑制劑所抑制。結果表示CRSBP-1 接合子可以刺激巨噬細胞移動及吞噬能力，這或許在動脈血管硬化疾病扮演關鍵的角色。而CRSBP-1 的拮抗劑和血小板生長因子β 型激酶抑制劑，則可以治療和預防動脈血管硬化疾病。 CRSBP-1 is a membrane receptor which mediates the phenomenon of cell-surface retention of growth factors (e.g., PDGF-BB and VEGF-A) after synthesis and secretion in cultured cells. The physiological function of CRSBP-1 is unknown. In our recent studies, we found that CRSBP-1-/Apo E- mice have lower risk of atherosclerosis disease than CRSBP-1+/Apo E- mice. This finding suggests that CRSBP-1 may play an important role in the pathogenesis of atherosclerosis. Since macrophages are known to be involved in the pathogenesis of atherosclerosis and since CRSBP-1 has recently been found to be expressed in macrophages, we hypothesize that CRSBP-1 and its ligands regulate migration and phagocytosis of macrophages in the process of the atherosclerosis disease. Here we demonstrate that the ligands of CRSBP-1 such as PDGF-BB and two specific ligands (PDGF-peptide and VEGF-peptide which specifically bind to CRSBP-1 and do not interact with the respective growth factor receptors of PDGF-BB and VEGF-A) stimulate migration and phagocytosis in RAW 264.7 cells, a macrophage-like cell line, and bone marrow–derived macrophages (BMM) with the optimal concentrations of 5-40 ng/mL, 10-20 uM and 10 μg/mL, respectively . The migration and phagocytosis are determined by scratch and Boyden chamber assays, and by measuring FITC-dextran uptake, respectively. VEGF-peptide appears to be more potent than PDGF-BB and PDGF-peptide in stimulating macrophage migration and phagocytosis at their optimal concentrations. The effects of these CRSB-1 ligands can be abolished in the presence of a PDGF β-type receptor kianse inhibitor. These results suggest that CRSBP-1 ligand-stimulated migration and phagocytosis of macrophages may play a pivotal role in the pathogenesis of atherosclerosis. These results also suggest that CRSBP-1antasgonists and PDGF β-type kinase inhibitors have potential to be therapeutic agents for treating and preventing atherosclerosis.
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