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Departments of Medicine (Division of Allergic Diseases) and Immunology, Mayo Clinic, Rochester, MN 55905; and
Department of Microbiology, QEII Medical Centre, University of Western Australia, Nedlands, Western Australia
Protease-activated receptors (PARs) are a unique class of G
protein-coupled receptors, which are activated by proteolytic cleavage
of the amino terminus of the receptor itself. PARs are most likely
involved in various biological responses, such as hemostasis and
regulation of muscle tone; however, the roles of PARs in the functions
of inflammatory and immune cells are poorly understood. Because
eosinophils are most likely involved in allergic inflammation and are
exposed to a variety of proteases derived from allergens and other
inflammatory cells, we investigated whether PARs regulate effector
functions of eosinophils. Human eosinophils constitutively transcribe
mRNA for PAR2 and PAR3, but not those for PAR1 and PAR4. The expression
of PAR2 protein was confirmed by flow cytometry. When trypsin, an
agonist for PAR2, was incubated with eosinophils, it potently induced
superoxide anion production and degranulation; 5 nM trypsin induced
responses that were 50
70% of those induced by 100 nM
platelet-activating factor, a positive control. In contrast, thrombin,
an activator for PAR1, PAR3, and PAR4, showed minimal effects. The
stimulatory effect of trypsin was dependent on its serine protease
activity and was blocked 59% by anti-PAR2 Ab. Furthermore, a
specific tethered peptide ligand for PAR2 potently induced superoxide
production and degranulation; the effects of peptide ligands for PAR1,
PAR3, and PAR4 were negligible. These findings suggest that human
eosinophils express functional PAR2, and serine proteases at the
inflammation site may play important roles in regulating effector
functions of human eosinophils. The expression and functional relevance
of other PARs still need to be determined.
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