Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells
Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells
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DOI：
10.1182/blood-2002-08-2497
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发表时间：
2003-10-01
期刊：
影响因子：
20.3
通讯作者：
Simmet, T
中科院分区：
文献类型：
--
作者：
Colognato, R;Slupsky, JR;Simmet, T
蛋白酶激活受体（PAR）通过其细胞外结构域的蛋白水解裂解来刺激，从而暴露作为拴系配体的新N-末端。尽管PAR在血小板中的作用是众所周知的，但其在人单核细胞和其他抗原呈递细胞中的存在和功能尚未被表征。在这里，它表明，人外周血单核细胞和单核细胞衍生的巨噬细胞和树突状细胞差异表达PAR。人单核细胞主要表达PAR 1，较少表达PAR 3。通过巨噬细胞集落刺激因子（M-CSF）或粒细胞-巨噬细胞集落刺激因子（GM-CSF）将单核细胞分化为巨噬细胞可增强PAR 1、PAR 2和PAR 3的表达。与此相反，树突状细胞分化的单核细胞的GM-CSF和白细胞介素-4（IL-4）强烈下调PAR 1，PAR 2和PAR 3，无论是在mRNA和蛋白质水平。PAR表达的下调显然是由于IL-4，因为用IL-4处理巨噬细胞引起PAR 1、PAR 2和PAR 3的下调。PAR 4 mRNA表达在所研究的任何细胞类型中均未检测到。用凝血酶、胰蛋白酶或已建立的受体激活肽（PAR-AP）刺激PAR 1、PAR 2和PAR 3触发胞质Ca 2+反应，表明功能活性PAR。此外，用凝血酶或PAR 1-AP而不是PAR 2-或PAR 4-AP刺激单核细胞或巨噬细胞，在mRNA和蛋白质水平上触发单核细胞趋化蛋白-1（MCP-1）的表达。这些数据表明，人单核细胞的分化与功能活性PAR的差异表达有关，PAR介导炎症和动脉粥样硬化形成中不同的调节功能。(C)2003年，美国血液学会。
Protease-activated receptors (PARs) are stimulated by proteolytic cleavage of their extracellular domain, unmasking a new N-terminus acting as tethered ligand. Whereas the role of PARs in platelets is well known, their presence and function in human monocytes and other antigen-presenting cells has not been characterized. Here it is demonstrated that human peripheral monocytes and monocyte-derived macrophages and dendritic cells differentially express PARs. Human monocytes express mainly PAR1 and less PAR3. Differentiation of monocytes into macrophages by either macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) elicits enhanced expression of PAR1, PAR2, and PAR3. In contrast, dendritic cells differentiated from monocytes by GM-CSF and interleukin-4 (IL-4) strongly down-regulated PAR1, PAR2, and PAR3, both at the mRNA and the protein level. Down-regulation of the PAR expression was apparently due to IL-4, because treatment of macrophages with IL-4 caused down-regulation of PAR1, PAR2, and PAR3. PAR4 mRNA expression remained undetectable in any of the cell types investigated. Stimulation of PAR1, PAR2, and PAR3 with thrombin, trypsin, or established receptor-activating peptides (PAR-APs) triggered cytosolic Ca2+ responses, indicating functionally active PARs. Further, stimulation of monocytes or macrophages with thrombin or PAR1-AP, but not with PAR2-or PAR4-AP, triggers expression of monocyte chemoattractant protein-1 (MCP-1) both at the mRNA and the protein level. These data demonstrate that differentiation of human monocytes is associated with differential expression of functionally active PARs that mediate distinct regulatory functions in inflammation and atherogenesis. (C) 2003 by The American Society of Hematology.