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

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Abstract
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.

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