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HUMAN MONOCYTES ACTIVATE PORCINE ENDOTHELIAL CELLS, RESULTING IN INCREASED E-SELECTIN, INTERLEUKIN-8, MONOCYTE CHEMOTACTIC PROTEIN-1, AND PLASMINOGEN ACTIVATOR INHIBITOR-TYPE-1 EXPRESSION1

1997; Wolters Kluwer; Volume: 63; Issue: 3 Linguagem: Inglês

10.1097/00007890-199702150-00016

1534-6080

Maria T. Millan, Carolyn L. Geczy, Karl M. Stuhlmeier, D.J. Goodman, Christiane Ferran, Fritz H. Bach,

Animal testing and alternatives

Monocytes (Mo) are thought to be important effector cells in early xenograft rejection. Effects of Mo-endothelial cell (EC) interactions on EC activation in vitro were studied by coculturing human Mo or human monocytoid cell lines, U937 and THP-1, with porcine EC. Without preactivation, U937 cells and Mo induced mRNA for the EC-specific adhesion receptor, E-selectin, expressed only on activated cells, after 2 hr. Surface protein was maximal when equal numbers of EC and Mo were cocultured. Increased mRNA expression of the chemokines, interleukin-8 and monocyte chemotactic protein-1, and the antifibrinolytic protein plasminogen activator inhibitor type-1, confirmed EC activation. Like E-selectin, plasminogen activator inhibitor type-1 mRNA was rapidly induced and returned to baseline after 24 hr, whereas chemokine gene expression was slower and more prolonged. Interleukin-1 receptor antagonist failed to modulate induction of E-selectin. Soluble tumor necrosis factor (TNF) α receptor inhibited E-selectin induced by TNFα, but not by U937 cells and mRNA and protein on EC in Mo-EC mixtures cocultured at 1:1 ratios were not significantly reduced. The TNFα inhibitor did reduce E-selectin expression (30-40%), as well as induced chemokine gene expression (80%), at higher Mo-EC ratios. Despite this, minimal TNFα was detectable in supernatants. These results, along with the transwell experiments that confirmed a requirement for Mo-EC contact, suggest that membrane-bound TNFα may be involved. Thus, Mo-EC interactions in the porcine to human combination activated several EC functions, suggesting that initial Mo contact with the vessel wall of a xenogeneic graft may promote leukocyte recruitment, inflammation, and maintenance of thrombus, resulting in eventual organ destruction.