Qiu Hong, Johansson Anne-Sofie, Sjöström Mattias, Wan Min, Schröder Oliver, Palmblad Jan, Haeggström Jesper Z
Department of Medical Biochemistry and Biophysics, Division of Chemistry II, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2006 May 2;103(18):6913-8. doi: 10.1073/pnas.0602208103. Epub 2006 Apr 19.
Leukotriene (LT) B4 is a powerful chemotactic and immune modulating agent that signals via two receptors denoted BLT1 and BLT2. Here we report that BLT1 and BLT2 are expressed at low levels in an apparently silent state in human umbilical vein endothelial cells (HUVEC). However, treatment with LPS leads to a >10 fold increase in the levels of BLT1 mRNA without any significant effects on BLT2 mRNA. In parallel, LPS also increases the amounts of BLT1 protein. Tumor necrosis factor-alpha (TNF-alpha) increases the expression of BLT2 mRNA approximately 6 times above basal levels with only a modest increase in BLT1 mRNA. Interleukin-1beta causes variable and parallel increases of both BLT1 and BLT2 mRNA. The natural ligand LTB4 also increases BLT1, but not BLT2, mRNA and protein expression. Along with the induction of BLT1 and/or BLT2, HUVEC acquire the capacity to respond to LTB4 with increased levels of intracellular calcium and these signals can be blocked by isotype selective BLT antagonists, CP-105696 and LY-255283. In addition, treatment of HUVEC with LTB4 causes increased release of both nitrite, presumably reflecting nitric oxide (NO), and monocyte chemoattractant protein-1. Our data indicate that expression of functional BLT receptors may occur at the surface of endothelial cells in response to LPS, cytokines, and ligand, which in turn may have functional consequences during the early vascular responses to inflammation. Moreover, the results point to BLT receptors as potential targets for pharmacological intervention in LT-dependent inflammatory diseases such as asthma, rheumatoid arthritis, and arteriosclerosis.
白三烯（LT）B4是一种强大的趋化和免疫调节剂，通过两种名为BLT1和BLT2的受体发出信号。在此我们报告，BLT1和BLT2在人脐静脉内皮细胞（HUVEC）中以明显沉默的状态低水平表达。然而，用脂多糖（LPS）处理会导致BLT1 mRNA水平增加10倍以上，而对BLT2 mRNA没有任何显著影响。同时，LPS也会增加BLT1蛋白的量。肿瘤坏死因子-α（TNF-α）使BLT2 mRNA的表达增加至基础水平的约6倍，而BLT1 mRNA仅适度增加。白细胞介素-1β会使BLT1和BLT2 mRNA产生可变且平行的增加。天然配体LTB4也会增加BLT1的mRNA和蛋白表达，但不会增加BLT2的。随着BLT1和/或BLT2的诱导，HUVEC获得了对LTB4作出反应的能力，细胞内钙水平升高，并且这些信号可被同型选择性BLT拮抗剂CP-105696和LY-255283阻断。此外，用LTB4处理HUVEC会导致亚硝酸盐（可能反映一氧化氮（NO））和单核细胞趋化蛋白-1的释放增加。我们的数据表明，功能性BLT受体的表达可能在内皮细胞表面因LPS、细胞因子和配体而发生，这反过来可能在炎症早期血管反应期间产生功能后果。此外，结果表明BLT受体是LT依赖性炎症性疾病（如哮喘、类风湿性关节炎和动脉硬化）药理干预的潜在靶点。
