MONOCYTE TETHERING BY P-SELECTIN REGULATES MONOCYTE CHEMOTACTIC PROTEIN-1 AND TUMOR-NECROSIS-FACTOR-ALPHA SECRETION - SIGNAL INTEGRATION AND NF-KAPPA-B TRANSLOCATION

Adhesion molecules that tether circulating leukocytes to endothelial c ells may also transduce or modulate outside-in signals for cellular ac tivation, providing an initial regulatory point in the inflammatory re sponse. Adhesion of human monocytes to P-selectin, the most rapidly ex pressed endothelial tethering factor, increased the secretion of monoc yte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF -alpha) by the leukocytes when they were stimulated with platelet-acti vating factor. Increased cytokine secretion was specifically inhibited by G1, an anti-P-selectin mAb that prevents P-selectin from binding t o its ligand (P-selectin glycoprotein ligand-1) on myeloid cells. More over, tethering by P-selectin specifically enhanced nuclear translocat ion of nuclear factor-kappa B (NF-kappa B), a transcription factor req uired for expression of MCP-1, TIVF-alpha, and other immediate-early g enes. These results demonstrate that P-selectin, through its ligands o n monocytes, may locally regulate cytokine secretion in inflamed tissu es.