Gaudreault Eric, Gosselin Jean
Viral Immunology Laboratory, CHUL Research Center (CHUQ) and Université Laval, Québec, PQ, G1V 4G2 Canada.
Viral Immunol. 2007 Sep;20(3):407-20. doi: 10.1089/vim.2006.0099.
Leukotriene B4 (LTB(4)) is a potent lipid mediator of inflammation that possesses antiviral activities. Here we provide evidence that LTB(4)-mediated defense against in vitro cytomegalovirus (CMV) infection of human leukocytes involves activation of the high-affinity LTB(4) receptor (BLT1) and neutrophil degranulation. Treatment of CMV-infected peripheral blood leukocytes with LTB(4) (10 nM) leads to a significant reduction in viral titers. This activity involves neutrophil activation through the BLT1 receptor, because no reduction in viral titers was observed after neutrophil depletion from cellular preparation or when leukocytes were pretreated with the BLT1 antagonist U75,302. Direct stimulation of neutrophils with LTB(4) (in the presence or absence of CMV) leads to the release of myeloperoxidase, alpha-defensins, eosinophil-derived neurotoxin, and the human cathelicidin LL-37 in a BLT1-dependent manner. LTB(4) does not act exclusively on the secretion of preformed antimicrobial peptides, but also acts on the synthesis of selected peptides as reflected by the increase in transcriptional levels of eosinophil-derived neurotoxin (EDN) and LL-37 in LTB(4)-treated neutrophils. Treatment of cell cultures with neutralizing antibodies directed against alpha-defensins, EDN, and LL-37 significantly reduces the antiviral effect of LTB(4), suggesting that LTB(4) may act through the release of antimicrobial peptides. Ex vivo experiments using LTB(4)-treated neutrophils from peritoneal washing of wild-type and BLT1 knockout mice further supported the role played by antimicrobial peptides in LTB(4)-mediated antiviral activity toward CMV. These results provide evidence of a mechanism by which LTB(4) induces host defense against viral infection.
白三烯B4（LTB4）是一种具有抗病毒活性的强效炎症脂质介质。在此我们提供证据表明，LTB4介导的针对人白细胞体外巨细胞病毒（CMV）感染的防御涉及高亲和力LTB4受体（BLT1）的激活和中性粒细胞脱颗粒。用LTB4（10 nM）处理CMV感染的外周血白细胞可导致病毒滴度显著降低。该活性涉及通过BLT1受体激活中性粒细胞，因为从细胞制剂中去除中性粒细胞后或用BLT1拮抗剂U75,302预处理白细胞后未观察到病毒滴度降低。用LTB4直接刺激中性粒细胞（无论有无CMV）会以BLT1依赖的方式导致髓过氧化物酶、α-防御素、嗜酸性粒细胞衍生神经毒素和人cathelicidin LL-37的释放。LTB4不仅作用于预先形成的抗菌肽的分泌，还作用于选定肽的合成，这体现在LTB4处理的中性粒细胞中嗜酸性粒细胞衍生神经毒素（EDN）和LL-37转录水平的增加。用针对α-防御素、EDN和LL-37的中和抗体处理细胞培养物可显著降低LTB4的抗病毒作用，表明LTB4可能通过释放抗菌肽发挥作用。使用来自野生型和BLT1基因敲除小鼠腹腔灌洗的LTB4处理的中性粒细胞进行的体外实验进一步支持了抗菌肽在LTB4介导的针对CMV的抗病毒活性中所起的作用。这些结果提供了LTB4诱导宿主抵抗病毒感染的机制的证据。
