Friedrich Erik B, Tager Andrew M, Liu Emerson, Pettersson Annika, Owman Christer, Munn Lance, Luster Andrew D, Gerszten Robert E
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown 02129, USA.
Arterioscler Thromb Vasc Biol. 2003 Oct 1;23(10):1761-7. doi: 10.1161/01.ATV.0000092941.77774.3C. Epub 2003 Aug 28.
Leukotriene B4 (LTB4) has been implicated in the trafficking of monocytes to inflammatory pathologic conditions, such as transplant rejection and atherosclerosis. The aim of this study was to determine the mechanisms by which LTB4 contributes to monocyte capture from the circulation.
In in vitro and in vivo vascular models, the lipid chemoattractant LTB4 was an equipotent agonist of monocyte adhesion compared with the chemokine monocyte chemoattractant protein-1 (MCP-1). Adenoviral gene transfer of specific endothelial adhesion molecules and blocking monoclonal antibody studies demonstrated that LTB4 triggers both beta1- and beta2-integrin-dependent adhesion. Flow cytometry studies suggested that changes in integrin avidity or affinity, rather than alterations of integrin surface expression, were responsible for the chemoattractant-triggered arrest. Surprisingly, in contrast to the peptide chemokine MCP-1, LTB4 did not activate the phosphoinositide 3-kinase pathway, which is a functionally critical step in chemokine-triggered effector functions.
LTB4 is a potent trigger of monocyte adhesion under flow yet mediates its effects via pathways that appear to differ from peptide chemoattractants. A better understanding of the mechanisms of LTB4-induced monocyte trafficking might shed insight into disease pathogenesis and pinpoint critical steps for therapeutic intervention for multiple human inflammatory pathologic conditions.
白三烯B4（LTB4）与单核细胞向炎症性病理状态（如移植排斥和动脉粥样硬化）的迁移有关。本研究的目的是确定LTB4促进单核细胞从循环中捕获的机制。
在体外和体内血管模型中，脂质趋化因子LTB4与趋化因子单核细胞趋化蛋白-1（MCP-1）相比，是单核细胞黏附的等效激动剂。特异性内皮黏附分子的腺病毒基因转移和阻断单克隆抗体研究表明，LTB4触发β1和β2整合素依赖性黏附。流式细胞术研究表明，趋化因子触发的单核细胞停滞是由整合素亲和力或亲合力的变化引起的，而不是整合素表面表达的改变。令人惊讶的是，与肽趋化因子MCP-1不同，LTB4不激活磷酸肌醇3激酶途径，而该途径是趋化因子触发效应功能的关键功能步骤。
LTB4是流动状态下单核细胞黏附的有效触发因子，但其作用机制似乎与肽趋化因子不同。更好地理解LTB4诱导单核细胞迁移的机制可能有助于深入了解疾病发病机制，并确定多种人类炎症性病理状态治疗干预的关键步骤。
