The attachment of leukocytes to endothelial cells is mediated by complementary adhesion molecules on the two cell types whose expression is enhanced by cytokines. Cytokines are secreted by cells in tissues in response to microbes and other injurious agents, thus ensuring that leukocytes are recruited to the tissues where these stimuli are present. The two major families of molecules involved in leukocyte adhesion and migration are the selectins and integrins (
Table 3.4 ). These molecules are expressed on leukocytes and endothelial cells, as are their ligands.
• Selectins mediate the initial weak interactions between leukocytes and endothelium. Selectins are receptors expressed on leukocytes and endothelium that contain an extracellular domain that binds sugars (hence the lectin part of the name). The three members of this family are E-selectin (also called CD62E), expressed on endothelial cells; P-selectin (CD62P), present on platelets and endothelium; and L-selectin (CD62L), found on the surface of most leukocytes. The ligands for selectins are sialic acid-containing oligosaccharides bound to glycoprotein backbones. The endothelial selectins are typically expressed at low levels or not at all on unactivated endothelium, and are upregulated after stimulation by cytokines and other mediators. Therefore, binding of leukocytes is largely restricted to the endothelium at sites of infection or tissue injury (where the mediators are produced). For example, in unactivated endothelial cells, P-selectin is found primarily in intracellular Weibel-Palade bodies; however, within minutes of exposure to mediators such as histamine or thrombin, P-selectin is distributed to the cell surface. Similarly, E-selectin and the ligand for L-selectin are expressed on endothelium only after stimulation by IL-1 and tumor necrosis factor (TNF), cytokines that are produced by tissue macrophages, dendritic cells, mast cells, and endothelial cells themselves following encounters with microbes and dead tissues. (These and other cytokines are described in more detail later.) Leukocytes express L-selectin at the tips of their microvilli and also express ligands for Eand P-selectins, all of which bind to the complementary molecules on the endothelial cells. These are low-affinity interactions with a fast off rate, and they are easily disrupted by the flowing blood. As a result, the bound leukocytes bind, detach, and bind again, and thus begin to roll along the endothelial surface. These weak selectin-mediated rolling interactions slow down the leukocytes and give them the opportunity to recognize additional adhesion molecules on the endothelium.
• Firm adhesion of leukocytes to endothelium is mediated by a family of leukocyte surface proteins called integrins. Integrins are transmembrane two-chain glycoproteins that mediate the adhesion of leukocytes to endothelium and of various cells to the extracellular matrix. They are normally expressed on leukocyte plasma membranes in a low-affinity form and do not adhere to their specific ligands until the leukocytes are activated by chemokines. Chemokines are chemoattractant cytokines that are secreted by many cells at sites of inflammation, bind to endothelial cell proteoglycans, and are displayed at high concentrations on the endothelial surface. When the rolling leukocytes encounter the displayed chemokines, the cells are activated, and their integrins undergo conformational changes and cluster together, thus converting to a high-affinity form. At the same time, other cytokines, notably TNF and IL-1, activate endothelial cells to increase their expression of ligands for integrins. These ligands include inter-cellular adhesion molecule-1 (ICAM-1), which binds to the integrins leukocyte function–associated antigen-1 (LFA-1) (also called CD11aCD18) and macrophage-1 http://ebooksmedicine.net