LEUKOCYTE-ENDOTHELIAL INTERACTIONS: IMPLICATIONS FOR INFLAMMATION AND COAGULATION

Abstract

A rapidly increasing body of data indicates that the vascular endothelium plays an active role in the development of inflammatory and thrombotic processes. Our laboratory has focused on the modulation of certain endothelial cell functions by inflammatory/immune mediators. Initially, we demonstrated that human monocyte derived interleukin-1 (hmIL-1) can act directly on cultured human endothelial cells (HEC) to increase the expression of tissue factor procoagulant activity in a time- and protein-synthesis dependent fashion (J. Exp. Med. 160:618, 1984). Increased expression of HEC tissue factor was also elicited with recombinant IL-1α (rlL-lα), rIL-1 β, and recombinant human tumor necrosis factor (rTNF), as well as with bacterial endotoxin (1 ipopolysaccharide, LPS) (Am. J. Pathol. 121:393, 1985; Proc. Natl. Acad. Sci. USA 83:4533, 1986). The kinetics of the HEC tissue factor responses to these stimuli were similar, demonstrating a rapid use rise to peak activity at ~ 4 hr, and a decline toward basal levels by 24 hr. This characteristic decline in tissue factor PCA after prolonged incubation with IL-1 or TNF was accompanied by selective endothelial hyporesponsiveness to the initially stimulating monokine. Interestingly, the effects of IL-1 and TNF were found to be additive even at apparent maximal doses of the individual monokines. We have also examined the effects of IL-1 and other mediators on HEC production of fibrinolytic components (J. Clin. Invest. 78:587, 1986). HEC monolayers which had been treated for 24 hr with IL-1 or TNF exhibited decreased tissue type plasminogen activator (tPA) and increased plasminogen activator inhibitor (PAI) as assessed in functional and immunological assays. Thus, certain inflammatory mediators such as IL-1 and TNF can act on vascular endothelial cells to induce the expression of tissue factor in a rapid and transient fashion, and to decrease the expression of fibrinolytic activity in a more prolonged fashion. In a parallel series of studies, we have demonstrated that IL-1, TNF and LPS also act on HEC to increase the adhesion of polymorphonuclear leukocytes (PMN), monocytes and the related cell lines HL-60 and U937 (J. Clin. Invest. 76:2003, 1985; Fed. Proc. 46:405A, 1987). The kinetics of this modulation of HEC adhesiveness parallel that of the change in tissue factor PCA. Recently, we have developed two monoclonal antibodies (mAb), H4/18 and H18/7, which identify a surface antigen expressed on monokine- and LPS-stimulated HEC but not on unstimulated HEC. The mediator specificity, kinetics, and protein synthesis-dependence of the expression of this antigen correlate with increased HEC adhesiveness for leukocytes. Neither mAb binds to unstimulated or stimulated PMN, HL-60 cells or dermal fibroblasts. H18/7 inhibits the adhesion of PMN (>50%) and HL-60 cells (>60%) to stimulated HEC by comparison to isotype matched control mAb; H4/18 also inhibits HL-60 adhesion but to a lesser extent. H4/18 and H18/7 immunoprecipitate the same polypeptides from biosynthetically-1abeled monokine-stimulated HEC, but not unstimulated HEC. We have designated this inducible endothelial cell surface protein, endothelial-leukocyte adhesion molecule-1 (E-LAM 1). Thus, vascular endothelium can be activated by inflammatory/immune mediators to express both prothrombotic and pro-inflammatory functions. In vivo, these endothelial responses may contribute to a variety of pathophysiologic processes.