Agonists of proteinase-activated receptor-2 modulate human neutrophil cytokine secretion, expression of cell adhesion molecules, and migration within 3-D collagen lattices

Proteinase-activated receptor-2 (PAR2) belongs to a novel subfamily of G-protein-coupled receptors with seven-transmembrane domains. PAR2 can be activated by serine proteases such as trypsin, mast cell tryptase, and allergic or bacterial proteases. This receptor is expressed by various cells and seems to be crucially involved during inflammation and the immune response. As previ- ously reported, human neutrophils express func- tional PAR2. However, the precise physiological role of PAR2 on human neutrophils and its impli- cation in human diseases remain unclear. We dem- onstrate that PAR2 agonist-stimulated human neu- trophils show significantly enhanced migration in 3-D collagen lattices. PAR2 agonist stimulation also induced down-regulation of L-selectin display and up-regulation of membrane-activated com- plex-1 very late antigen-4 integrin expression on the neutrophil cell surface. Moreover, PAR2 stim- ulation results in an increased secretion of the cy- tokines interleukin (IL)-1, IL-8, and IL-6 by hu- man neutrophils. These data indicate that PAR2 plays an important role in human neutrophil acti- vation and may affect key neutrophil functions by regulating cell motility in the extracellular matrix, selectin shedding, and up-regulation of integrin ex- pression and by stimulating the secretion of inflam- matory mediators. Thus, PAR2 may represent a potential therapeutic target for the treatment of diseases involving activated neutrophils. J. Leukoc. Biol. 76: 388-398; 2004.