THE EFFECT OF INTERLEUKIN-4 ON TUMOR-NECROSIS-FACTOR-ALPHA INDUCED EXPRESSION OF TISSUE FACTOR AND PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN HUMAN UMBILICAL VEIN ENDOTHELIAL-CELLS

The pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) is able to alter the haemostatic balance of human umbilical vein endo thelial cells (HUVECs) towards that of a procoagulant and anti-fibrino lytic state. Treatment of HUVECs in culture with human recombinant TNF -alpha (0.5-50 U/ml; 6 h) significantly increased total cell expressio n of tissue factor (TF) 10-fold from 40 mU/well to 400-500 mU/well. Le vels of plasminogen activator inhibitor-1 (PAI-1) antigen secreted fro m HUVECs also increased up to 2-fold in concentration-dependent fashio n following addition of TNF-alpha (10-100 U/ml; 24 h). TNF-alpha induc ed 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. Pretreat ment of HUVECs with IL-4 for 4 h had no significant effect, but increa sing inhibition of total TF expression occurred after 8 and 16 h pre-i ncubations. Treatment with IL-4 at 20 and 200 U/ml significantly inhib ited cell surface TF responses induced by TNF-alpha, whereas a low con centration (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, IL4 may regulate the pro-coagulant but not the antifibrinolytic effects of TNF-alpha at sites of vascular inflammation.