Li Geling, Kim Young-June, Mantel Charlie, Broxmeyer Hal E
Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
J Immunol. 2003 Jul 15;171(2):669-77. doi: 10.4049/jimmunol.171.2.669.
Endothelial cells play a critical role in monocyte differentiation. Platelets also affect terminal maturation of monocytes in vitro. P-selectin is an important adhesion molecule expressed on both endothelial cells and activated platelets. We investigated its effects on human peripheral blood monocyte differentiation under the influence of different cytokines. Generation of dendritic-like cells (DLCs) from peripheral blood monocytes was promoted by immobilized P-selectin in the presence of M-CSF and IL-4 as judged by dendritic cell (DC) morphology; increased expression of CD1a, a DC marker; low phagocytic activity; and high alloreactivity to naive T cells. In contrast to typical DCs, DLCs expressed CD14 and FcgammaRIII (CD16). These features link the possible identity of DLCs to that of an uncommon CD14(+)CD16(+)CD64(-) monocyte subset found to be expanded in a variety of pathological conditions. Functionally, DLCs generated by P-selectin in combination with M-CSF plus IL-4 primed naive allogeneic CD4(+) T cells to produce significantly less IFN-gamma than cells generated by BSA in the presence of M-CSF and IL-4. P-selectin effects on enhancing CD14(+)CD16(+) DLC generation were completely abrogated by pretreatment of cells with the protein kinase C delta inhibitor rottlerin, but not by classical protein kinase C inhibitor Gö6976. Immobilized P-selectin also inhibited macrophage differentiation in response to M-CSF alone as demonstrated by morphology, phenotype, and phagocytosis analysis. The effects of P-selectin on macrophage differentiation were neutralized by pretreatment of monocytes with Ab against P-selectin glycoprotein ligand 1. These results suggest a novel role for P-selectin in regulating monocyte fate determination.
内皮细胞在单核细胞分化中起关键作用。血小板在体外也会影响单核细胞的终末成熟。P-选择素是在内皮细胞和活化血小板上均表达的一种重要黏附分子。我们研究了其在不同细胞因子影响下对人外周血单核细胞分化的作用。通过树突状细胞（DC）形态学判断，在M-CSF和IL-4存在的情况下，固定化的P-选择素可促进外周血单核细胞生成树突状样细胞（DLC）；DC标志物CD1a的表达增加；吞噬活性低；对初始T细胞的同种异体反应性高。与典型DC不同，DLC表达CD14和FcγRIII（CD16）。这些特征将DLC可能的身份与在多种病理条件下发现扩增的罕见CD14(+)CD16(+)CD64(-)单核细胞亚群联系起来。在功能上，P-选择素与M-CSF加IL-4联合产生的DLC对初始同种异体CD4(+)T细胞的启动作用，使其产生的IFN-γ明显少于在M-CSF和IL-4存在下BSA产生的细胞。用蛋白激酶Cδ抑制剂rottlerin预处理细胞可完全消除P-选择素对增强CD14(+)CD16(+)DLC生成的作用，但经典蛋白激酶C抑制剂Gö6976则无此作用。通过形态学、表型和吞噬作用分析表明，固定化的P-选择素也可抑制单核细胞对单独M-CSF的巨噬细胞分化反应。用抗P-选择素糖蛋白配体1的抗体预处理单核细胞可中和P-选择素对巨噬细胞分化的作用。这些结果表明P-选择素在调节单核细胞命运决定中具有新作用。
