Serio Kenneth J, Johns Scott C, Luo Linda, Hodulik Craig R, Bigby Timothy D
Department of Medicine, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
J Immunol. 2003 Feb 15;170(4):2121-8. doi: 10.4049/jimmunol.170.4.2121.
We studied the effects of LPS on cysteinyl leukotriene (LT) synthesis and LTC(4) synthase expression in mononuclear phagocytes. Conditioning of the monocyte-like cell line, THP-1, with LPS for 7 days resulted in significantly decreased ionophore-stimulated LTC(4) release. The putative LPS receptor, Toll-like receptor 4, was expressed in THP-1 cells. LPS down-regulated LTC(4) synthase mRNA in THP-1 cells in a dose- and time-dependent manner, with down-regulation observed as early as 4 h. Conditioning of actinomycin D-treated cells with LPS resulted in no change in the rate of LTC(4) synthase mRNA decay. LPS treatment of THP-1 cells, transiently transfected with a LTC(4) synthase promoter (1.35 kb)-reporter construct, decreased promoter activity. Neutralization of TNF-alpha and inhibition of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase did not inhibit the effect of LPS. Treatment of cells with a Toll-like receptor 4-blocking Ab and an inhibitor of NF-kappaB activation resulted in inhibition of the LPS effect, while activation of NF-kappaB and p50/p65 overexpression down-regulated the LTC(4) synthase gene. LPS down-regulates cysteinyl LT release and LTC(4) synthase gene expression in mononuclear phagocytes by an NF-kappaB-mediated mechanism.
我们研究了脂多糖（LPS）对单核吞噬细胞中半胱氨酰白三烯（LT）合成及白三烯C4（LTC4）合酶表达的影响。用LPS处理单核细胞样细胞系THP-1 7天，可使离子载体刺激的LTC4释放显著减少。假定的LPS受体Toll样受体4在THP-1细胞中表达。LPS以剂量和时间依赖性方式下调THP-1细胞中的LTC4合酶mRNA，早在4小时就观察到下调。用LPS处理经放线菌素D处理的细胞，LTC4合酶mRNA的衰变率没有变化。用LTC4合酶启动子（1.35 kb）-报告基因构建体瞬时转染的THP-1细胞经LPS处理后，启动子活性降低。中和肿瘤坏死因子-α（TNF-α）以及抑制丝裂原活化蛋白激酶激酶/细胞外信号调节激酶并不能抑制LPS的作用。用Toll样受体4阻断抗体和NF-κB激活抑制剂处理细胞可抑制LPS的作用，而激活NF-κB以及过表达p50/p65可下调LTC4合酶基因。LPS通过NF-κB介导的机制下调单核吞噬细胞中半胱氨酰LT的释放及LTC4合酶基因的表达。
