IL-1-induced adhesion of polymorphonuclear leukocytes to cultured human endothelial cells. Role of platelet-activating factor.
In early studies we found that IL-1 stimulated endothelial cells (EC) to produce platelet-activating factor (PAF, 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine). Inasmuch as this phospholipid has a wide range of biologic activities, including polymorphonuclear leukocytes (PMN) aggregation and chemotaxis, we investigated whether EC-associated PAF could contribute to IL-1-induced PMN adhesion to EC. When four selective PAF antagonists were added to IL-1-stimulated EC during the PMN adhesion assay, adhesion was reduced in a concentration-related way. Similarly, pre-treatment of PMN with PAF before the adhesion assay to induce desensitization to this phospholipid reduced PMN adhesion to IL-1-treated EC. However, comparing the time course and the concentration response curve of IL-1-induced EC adhesivity and PAF synthesis, we found that increased EC adhesivity to PMN required a shorter incubation time and lower concentration of IL-1 to become apparent than PAF production. When acetyl-coenzyme A was added to EC cultures at a concentration that raised PAF synthesis by 60%, no significant increase in PMN adhesion was observed. In addition, after 9 to 10 doublings, the EC ability to synthesize PAF decreased by 85 to 90%, whereas IL-1-induced EC adhesivity to PMN was only slightly diminished. When IL-1-alpha and -beta were tested on EC, we observed that both were equally active in promoting PMN adhesion to EC but only the alpha-form was able to stimulate PAF production. When PMN were seeded on IL-1-treated EC, increased amounts of PAF were detected even when EC were fixed; in addition, the inhibitory effect of a PAF antagonist was evident also in these conditions. Overall these results indicate that IL-1-induced PAF production by EC does not significantly contribute to PMN adhesion to them. We hypothesize that the observed inhibitory effect of PAF antagonists and PAF desensitization of PMN might be directed at PAF produced by PMN themselves during adhesion to IL-1-treated EC.
Breviario
F
F
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Bertocchi
F
F
Dejana
E
E
Bussolino
F
F
D002448:Cell Adhesion / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
D007375:Interleukin-1; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins