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 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.
Shpacovitch
V M
VM
Department of Dermatology, University of Münster, von-Esmarch-Str. 58, 48149 Münster, Germany.
Varga
G
G
Strey
A
A
Gunzer
M
M
Mooren
F
F
Buddenkotte
J
J
Vergnolle
N
N
Sommerhoff
C P
CP
Grabbe
S
S
Gerke
V
V
Homey
B
B
Hollenberg
M
M
Luger
T A
TA
Steinhoff
M
M
D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000378:metabolism*; D044462:Receptors, Proteinase-Activated / Q000819:agonists*; D015854:Up-Regulation
D015815:Cell Adhesion Molecules; D016207:Cytokines; D007378:Interleukins; D044462:Receptors, Proteinase-Activated; D019041:L-Selectin; D002118:Calcium