Martin N B, Jamieson A, Tuffin D P
Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
Thromb Haemost. 1993 Dec 20;70(6):1037-42.
The pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) is able to alter the haemostatic balance of human umbilical vein endothelial cells (HUVECs) towards that of a procoagulant and anti-fibrinolytic state. Treatment of HUVECs in culture with human recombinant TNF-alpha (0.5-50 U/ml; 6 h) significantly increased total cell expression of tissue factor (TF) 10-fold from 40 mU/well to 400-500 mU/well. Levels of plasminogen activator inhibitor-1 (PAI-1) antigen secreted from HUVECs also increased up to 2-fold in concentration-dependent fashion following addition of TNF-alpha (10-100 U/ml; 24 h). TNF-alpha induced total and cell surface expression of TF on HUVECs was significantly inhibited when the cells were pre-incubated with interleukin-4 (IL-4; p < 0.001). This effect was time and concentration dependent. Pretreatment of HUVECs with IL-4 for 4 h had no significant effect, but increasing inhibition of total TF expression occurred after 8 and 16 h pre-incubations. Treatment with IL-4 at 20 and 200 U/ml significantly inhibited cell surface TF responses induced by TNF-alpha, whereas a low concentration (0.2 U/ml) was without effect. In contrast, the production of PAI-1 from HUVECs stimulated by TNF-alpha (50 U/ml) was unaffected by the presence and/or prior incubation with 200 U/ml IL-4. Thus, IL-4 may regulate the pro-coagulant but not the antifibrinolytic effects of TNF-alpha at sites of vascular inflammation.
促炎细胞因子肿瘤坏死因子-α（TNF-α）能够使人脐静脉内皮细胞（HUVECs）的止血平衡向促凝血和抗纤溶状态转变。用人重组TNF-α（0.5 - 50 U/ml；6小时）处理培养中的HUVECs，可使组织因子（TF）的总细胞表达量从40 mU/孔显著增加10倍，达到400 - 500 mU/孔。添加TNF-α（10 - 100 U/ml；24小时）后，HUVECs分泌的纤溶酶原激活物抑制剂-1（PAI-1）抗原水平也以浓度依赖的方式增加了2倍。当细胞与白细胞介素-4（IL-4；p < 0.001）预孵育时，TNF-α诱导的HUVECs上TF的总表达和细胞表面表达受到显著抑制。这种作用具有时间和浓度依赖性。用IL-4预处理HUVECs 4小时没有显著影响，但在预孵育8小时和16小时后，对TF总表达的抑制作用增强。用20和200 U/ml的IL-4处理可显著抑制TNF-α诱导的细胞表面TF反应，而低浓度（0.2 U/ml）则无效。相反，TNF-α（50 U/ml）刺激的HUVECs产生PAI-1不受200 U/ml IL-4存在和/或预先孵育的影响。因此，在血管炎症部位，IL-4可能调节TNF-α的促凝血作用，但不调节其抗纤溶作用。
