Leukocyte activation and adhesion to the endothelium are pivotal steps in the recruitment of cells to the inflamed tissue. This coordinated sequence of adhesive events on the endothelium includes the rolling, the leukocyte activation, the firm adhesion to and subsequent locomotion and the trans-endothelial migration. During trans-endothelial migration, molecules located at the interendothelial junctions may facilitate the passage of the transmigrating leukocyte. We have recently identified the third member of the JAM family, junctional adhesion molecule-C (JAM-C), and could demonstrate that JAM-C is expressed at the interendothelial junctions and serves as a counter-receptor for neutrophil Mac-1, mediating the transendothelial migration of the neutrophils in vitro and in vivo. In contrast, JAM-C does not participate in the adhesion of leukocytes to quiescent endothelial cells, as it is located at the interendothelial junctions and is not available for leukocyte integrin Mac-1. In addition, to the heterophilic interaction of JAM-C with Mac-1, we also identified JAM-C to interact homophilically. We could characterize the biochemical properties of this interaction. Through the homophilic interaction of JAM-C, lung carcinoma cells adhered to endothelial cells. Moreover, we have recently found that JAM-C regulates endothelial paracellular permeability. In contrast to other transmembrane molecules of the endothelial junctions that act as gatekeepers, JAM-C was identified as the first molecule to mediate an increase in paracellular permeability. JAM-C regulates the activity of the small GTPase rap1 and thereby the integrity of adherens junctions. Moreover, JAM-C in endothelial cells facilitates stress fiber formation. JAM-C inhibition in vivo blocks the VEGF or histamine induced permeability as well as hypoxia-driven retina angiogenesis. Our current investigations include: a) By regulating VE-cadherin-mediated adherens junctions and vascular endothelial permeability JAM-C could also modulate inflammatory cell recruitment. The importance of JAM-C in leukocyte transendothelial migration in vivo is tested with the use of JAM-C -/- mice, by using several inflammation models, such as chemical peritonitis, lung inflammation and experimental autoimmune encephalomyelitis. b) The homophilic interaction of JAM-C mediates tumor cell adhesion to the endothelium. By using the JAM-C ko mice, tumor (specifically melanoma) metastasis is studied. In addition a mouse carrying a mutant form of JAM-C incapable of interacting homophilically is currently generated to be included in these studies.
