Juxtacrine interactions of endothelial cells with leukocytes: tethering and signaling molecules.

The interaction of blood leukocytes with the endothelium of post-capillary venules and other vessels involves regulated expression of molecules on both the endothelial cell (EC) and the leukocyte. This is true for each of the major classes of leukocytes, including lymphocytes, monocytes, and granulocytes. Interaction of polymorphonuclear leukocytes (PMNs), a particular subset of granulocytes, with cultured human endothelium illustrates this concept and also illustrates the diversity of structure, mechanisms of expression, and mechanisms of action of the molecules involved. One group of molecules binds, or "tethers", the PMN to the EC without requiring PMN activation; P-selectin and E-selectin, which are glycoproteins that are expressed by translocation from subcellular granules or synthesis under transcriptional regulation, respectively, are examples. A second group of molecules activates the PMN by binding to signal-transducing receptors. Platelet-activating Factor (PAF), a biologically-active phospholipid, is an example of this class. Its production is controlled by regulation of synthetic enzymes and is induced rapidly (minutes) when EC are appropriately stimulated. PAF is translocated to the EC surface, where it mediates juxtacrine activation of PMNs by binding to a "7 membrane-spanning" receptor. One consequence of juxtacrine activation of PMNs by PAF is functional upregulation of CD11/CD18 integrins on the PMN. These integrins bind to counterreceptors on the EC, enhancing the avidity of adhesion over that provided by P-selectin alone. Thus, combinations of tethering and signaling molecules regulate PMN adhesive interactions with EC. Combinations of such molecules also regulate other functional responses of the PMNs that are important in inflammation. The time-dependent expression of different patterns of tethering and signaling molecules by EC provides a general mechanism for differential adhesion and activation of different classes leukocytes in acute and subacute inflammation.