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

Abstract

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 previously reported, human neutrophils express functional PAR2. However, the precise physiological role of PAR2 on human neutrophils and its implication in human diseases remain unclear. We demonstrate that PAR2 agonist-stimulated human neutrophils 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 complex-1 very late antigen-4 integrin expression on the neutrophil cell surface. Moreover, PAR2 stimulation results in an increased secretion of the cytokines interleukin (IL)-1beta, IL-8, and IL-6 by human neutrophils. These data indicate that PAR2 plays an important role in human neutrophil activation and may affect key neutrophil functions by regulating cell motility in the extracellular matrix, selectin shedding, and up-regulation of integrin expression and by stimulating the secretion of inflammatory mediators. Thus, PAR2 may represent a potential therapeutic target for the treatment of diseases involving activated neutrophils.

Agonists of Proteinase-Activated Receptor-2 Enhance IFN-γ-Inducible Effects on Human Monocytes: Role in Influenza A Infection

“…Previously, it was demonstrated that cAP induces an increase in [Ca 2ϩ ] i in human neutrophils (16). Human primary monocytes are known to express PAR 2 mRNA (17,18), and, in our study, we wanted to confirm that cAP is able to activate PAR 2 expressed by human monocytes.…”

“…Trypsin was purchased from Sigma-Aldrich. Human PAR 2 activating peptide with the sequence transcinnamoyl-LIGRLO-NH 2 (cAP) and reverse peptide with sequence transcinnamoyl-OLRGIL-NH 2 (cRP) (from Dr. McMaster, University of Calgary, Calgary, Canada) were used as described previously (16). The following mAbs were used: unconjugated mouse anti-human PAR 2 (clone SAM-11) (Santa Cruz Biotechnology), mouse anti-human CD64 (Dako), mouse anti-human ␣V␤3 (Chemicon International), mouse anti-human IB␣ (Imgenex), as well as mouse anti-human ␤-Actin (Sigma-Aldrich).…”

Protease-Activated Receptor-2 Activation Induces Acute Lung Inflammation by Neuropeptide-Dependent Mechanisms

“…PAR2 is also expressed on mouse microvascular endothelial cells (34), and PAR2 may be expressed by and contribute to a variety of functions in human neutrophils (35,36). Thus, a direct effect of PAR2-AP on neutrophils might contribute to increased MPO activity and MDA levels in plasma, and perhaps additional responses in the lung in these studies.…”

Membrane-Type Serine Protease-1/Matriptase Induces Interleukin-6 and -8 in Endothelial Cells by Activation of Protease-Activated Receptor-2

“…35 Recent studies identified proinflammatory effects of PAR-2 activation in neutrophils. 36 Moreover, in vivo studies in PAR-2-deficient mice highlight the critical roles of PAR-2 in skin progression and joint inflammation as well as sepsis. 37,38 In vascular disease, PAR-2-derived peptide agonists reduce vascular tone and increase blood flow via nitric oxide-dependent and -independent actions of the endothelium.…”