HUMAN ENDOTHELIAL-CELLS SYNTHESIZE ENA-78 - RELATIONSHIP TO IL-8 AND TO SIGNALING OF PMN ADHESION

The interaction of endothelial cells and polymorphonuclear leukocytes (PMNs, neutrophils) is a critical determinant of the acute inflammator y response, and mirrors cell-cell interactions in other biologic syste ms, Adhesion molecules that tether the two cells together, and signali ng factors that bind to receptors on the leukocytes and mediate their spatially-localized activation, govern PMN responses as they adhere to and traverse stimulated endothelial cells. Here we show that cultured human endothelial cells express two members of the C-X-C family of ch emokines, epithelial neutrophil activating peptide-78 (ENA-78) and int erleukin (IL)-8, when stimulated by IL-1 or certain other agonists. EN A-78, previously thought to be exclusively a product of epithelium, is expressed by in situ endothelium in inflamed human lung and other tis sues as well as by cultured endothelial cells, The regulation of ENA-7 8 and IL-8 share certain features in common and they have overlapping biologic activities, including the ability to induce PMN adhesiveness. This was demonstrated in experiments in which sie found that ENA-78 i nduces inside-out signaling of beta(2) integrins on the PMN surface, a s does IL-8. Antibody blocking experiments demonstrated that ENA-78 co ntributes to the proadhesive activity for neutrophils that is released by endothelial cells stimulated with IL-1 for a prolonged period and that it acts in concert with IL-8, which provides the major component of the signal for adhesion under this condition, We also show, however , that the temporal expression and secretion of ENA-78 and other chara cteristics of its handling by stimulated endothelial cells vary from t he expression of IL-8, indicating that differential regulation of the two signaling chemokines occurs in this cell type.