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,,1
* Department of Pediatrics,
Institute of Experimental Dermatology,
Department of Dermatology, University of Münster, Germany;
Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania, USA;
|| Department of Pharmacology, University of Calgary, Canada;
¶ Departments of Surgery & Physiology, UCSF, San Francisco, California, USA;
** Department of Cell Biology, Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Germany;
Department of Physiology, University of Erlangen, Germany; and
Department of Physiology, University of Calgary, Canada
1Correspondence: Department of Dermatology, University of Münster, von-Esmarch-Str. 58, 48129 Münster, Germany. E-mail: msteinho{at}uni-muenster.de
Proteinase-activated receptor-2 belongs to a new subfamily of G-protein-coupled receptors. Its precise role during inflammation and the underlying mechanisms is still unclear. Our study establishes that PAR-2 plays a direct proinflammatory role during cutaneous inflammation in mice and humans in vivo. In a model of experimentally induced allergic (ACD) and toxic (ICD) contact dermatitis (CD) we show that ear swelling responses, plasma extravasation, and leucocyte adherence were significantly attenuated in PAR-2 null mutant (PAR-2-/-) mice compared with wild-type (PAR-2+/+) mice, especially at early stages. The proinflammatory effects by PAR-2 activation were significantly diminished using nitric oxide-synthase inhibitors, while NF-kappaB and neuropeptides appear to play a minor role in these mechanisms. PAR-2-mediated up-regulation of E-selectin and cell adhesion molecule ICAM-1; enhanced plasma extravasation was observed in humans and mice and of interleukin-6 in mice in vivo. Thus, PAR-2 may be a beneficial therapeutic target for the treatment of inflammatory skin diseases.—Seeliger, S., Derian, C. K., Vergnolle, N., Bunnett, N. W., Nawroth, R., Schmelz, M., von der Weid, P.-Y., Buddenkotte, J., Sunderkötter, C., Metze, D., Andrade-Gordon, P., Harms, E., Vestweber, D., Luger, T. A., Steinhoff, M. Proinflammatory role of proteinase-activated receptor-2 in humans and mice during cutaneous inflammation in vivo.
Key Words: proteinase-activated receptors • G-protein-coupled receptors • immune response • knockout mouse • skin
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