Curbishley Stuart M, Eksteen Bertus, Gladue Ron P, Lalor Patricia, Adams David H
Liver Research Group, Institute of Biomedical Research, MRC Centre for Immune Regulation, The University of Birmingham Medical School, Edgbaston, Birmingham, UK B15 2TT.
Am J Pathol. 2005 Sep;167(3):887-99. doi: 10.1016/S0002-9440(10)62060-3.
T cells infiltrating the inflamed liver express high levels of CXCR 3 and show enhanced migration to CXCR 3 ligands in chemotactic assays. Moreover, CXCR 3 ligands are up-regulated on hepatic endothelium at sites of T-cell infiltration in chronic hepatitis, and their presence correlates with outcome of inflammatory liver disease. We used a flow-based adhesion assay with human hepatic endothelium to investigate the function of CXCR 3 on lymphocyte adhesion to and transmigration through hepatic endothelium under physiological conditions of blood flow. To more accurately model the function of in vivo activated CXCR 3(high) lymphocytes, we isolated T cells from human liver tissue and studied their behavior in flow-based adhesion assays. We demonstrate that CXCR 3 not only promoted the adhesion of effector T cells to endothelium from flow but also drove transendothelial migration. Moreover, these responses could be stimulated either by endogenous CXCR 3 ligands secreted by the endothelium or by exogenous CXCR 3 ligands derived from other cell types and presented by the endothelium. This study thus demonstrates that activation of CXCR 3 promotes lymphocyte adhesion and transendothelial migration under flow and that human hepatic endothelium can present functionally active chemokines secreted by other cell types within the liver.
浸润炎症肝脏的T细胞表达高水平的CXCR 3，并在趋化试验中显示出对CXCR 3配体增强的迁移能力。此外，在慢性肝炎T细胞浸润部位的肝内皮细胞上，CXCR 3配体上调，其存在与炎症性肝病的预后相关。我们使用基于流动的人肝内皮细胞黏附试验，来研究在生理血流条件下CXCR 3对淋巴细胞黏附于肝内皮细胞及穿过肝内皮细胞迁移的功能。为了更准确地模拟体内活化的CXCR 3（高表达）淋巴细胞的功能，我们从人肝组织中分离出T细胞，并在基于流动的黏附试验中研究它们的行为。我们证明，CXCR 3不仅促进效应T细胞从流动状态黏附于内皮细胞，还驱动其跨内皮迁移。此外，这些反应可以由内皮细胞分泌的内源性CXCR 3配体，或由其他细胞类型产生并由内皮细胞呈递的外源性CXCR 3配体所刺激。因此，本研究表明，CXCR 3的激活促进了血流状态下淋巴细胞的黏附和跨内皮迁移，并且人肝内皮细胞能够呈递肝脏内其他细胞类型分泌的具有功能活性的趋化因子。
