Proinflammatory role of proteinase-activated receptor-2 in humans and mice during cutaneous inflammation in vivo

Stephan Seeliger, Claudia K. Derian, Nathalie Vergnolle, Nigel W. Bunnett, Roman Nawroth, Martin Schmelz, Pierre Yves Von der Weid, Jörg Buddenkotte, Cord Sunderkötter, Dieter Metze, Patricia Andrade-Gordon, Erik Harms, Dietmar Vestweber, Thomas A. Luger, Martin Steinhoff

Research output: Contribution to journalArticlepeer-review

Abstract

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 upregulation 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.

Original languageEnglish (US)
Pages (from-to)1871-1885
Number of pages15
JournalFASEB Journal
Volume17
Issue number13
DOIs
StatePublished - Oct 2003

Keywords

  • G-protein-coupled receptors
  • Immune response
  • Knockout mouse
  • Proteinase-activated receptors
  • Skin

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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