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Published online before print May 20, 2004

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(Journal of Leukocyte Biology. 2004;76:388-398.)
© 2004 by Society for Leukocyte Biology

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

V. M. Shpacovitch^*, G. Varga^*, A. Strey, M. Gunzer^*, F. Mooren, J. Buddenkotte^*, N. Vergnolle, C. P. Sommerhoff^¶, S. Grabbe^*, V. Gerke, B. Homey^||, M. Hollenberg, T. A. Luger^* and M. Steinhoff^*,1

^* Department of Dermatology and Ludwig Boltzmann Institute for Cell- and Immunobiology of the Skin and Institutes of
Biochemistry, ZMBE, and
Sport Medicine, University of Muenster, Germany;
^¶ Department of Clinical Chemistry & Clinical Biochemistry, University of Munich, Germany;
Department of Pharmacology and Therapeutics, University of Calgary, Alberta, Canada; and
^|| Department of Dermatology, University of Düsseldorf, Germany

¹Correspondence: Department of Dermatology and Ludwig Boltzmann Institute for Immunobiology of the Skin, University of Münster, von-Esmarch-Str. 58, 48149 Münster, Germany. E-mail: msteinho{at}uni-muenster.de

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)-1ß, 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.

Key Words: proteinases • leukocytes • extracellular matrix • interleukins • G-protein coupled receptors

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