HUMAN ENDOTHELIAL-CELLS REGULATE POLYMORPHONUCLEAR LEUKOCYTE DEGRANULATION

Neutrophil degranulation is an important event in inflammatory respons es. We examined the regulation of neutrophil (PMN) degranulation by re sting and activated human endothelial cells. Whereas PMNs adherent to endothelial cells that were stimulated to express P-selectin and plate let-activating factor did not release the specific granule marker lact oferrin or the primary granule enzyme, elastase, PMNs adherent to endo thelial cells stimulated with interleukin-1 (IL-1) or tumor necrosis f actor secreted both. PMN degranulation was dependent on the time of in cubation of endothelial cells with the cytokine, its concentration, an d the time of incubation of the PMNs with endothelial cells. Degranula tion of PMNs and their adhesion to stimulated endothelial cells are co rrelated events, but they could be dissociated by blocking the tetheri ng molecules used by the endothelial cells and neutrophils under these conditions. This suggested that paracrine signaling molecules that in duce PMN degranulation are produced by cytokine-stimulated endothelial cells. We found that endothelial cells stimulated with IL-1 release n ewly synthesized degranulating factors that require transcription and translation. IL-8 was synthesized, released, and signaled granular sec retion by PMNs, However, experiments with blocking antibodies indicate d the presence of an additional degranulating factor not accounted for by IL-8. These experiments demonstrate that human endothelial cells r egulate degranulation of neutrophils by generating signaling factors t hat are expressed differentially depending on the endothelial agonist and other features. Active modification of neutrophil granular secreti on by endothelial cells can influence physiologic acute inflammatory r esponses but may also contribute to pathologic vascular and tissue dam age.