Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis

Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13936-41. doi: 10.1073/pnas.241377298.

Abstract

The proteinase-activated receptor 2 (PAR-2) is a member of a family of G protein-coupled receptors for proteases. Proteases cleave PARs within the extracellular N-terminal domains to expose tethered ligands that bind to and activate the cleaved receptors. PAR-2 is highly expressed in colon in epithelial and neuronal elements. In this study we show that PAR-2 activation prevents the development and induces healing of T helper cell type 1-mediated experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. A role for PAR-2 in the protection against colon inflammation was explored by the use of SLIGRL-NH(2), a synthetic peptide that corresponds to the mouse tethered ligand exposed after PAR-2 cleavage. TNBS-induced colitis was dose-dependently reduced by the administration of SLIGRL-NH(2), whereas the scramble control peptide, LSIGRL-NH(2), was uneffective. This beneficial effect was reflected by increased survival rates, improvement of macroscopic and histologic scores, decrease in mucosal content of T helper cell type 1 cytokines, protein, and mRNA, and a diminished myeloperoxidase activity. SLIGRL-NH(2), but not the scramble peptide, directly inhibited IFN-gamma secretion and CD44 expression on lamina propria T lymphocytes. Protection exerted by PAR-2 in TNBS-treated mice was reverted by injecting mice with a truncated form of calcitonin gene-related peptide and by sensory neurons ablation with the neurotoxin capsaicin. Collectively, these studies show that PAR-2 is an anti-inflammatory receptor in the colon and suggest that PAR-2 ligands might be effective in the treatment of inflammatory bowel diseases.

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / pharmacology
  • Capsaicin / pharmacology
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / immunology*
  • Colitis / pathology
  • Colitis / prevention & control
  • Colon / cytology
  • Colon / immunology*
  • Disease Models, Animal
  • Down-Regulation
  • Enzyme Activation
  • Hyaluronan Receptors / biosynthesis
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / biosynthesis
  • Interleukin-2 / biosynthesis
  • Mice
  • Mice, Inbred BALB C
  • Oligopeptides / pharmacology
  • Peptide Fragments / pharmacology
  • Receptor, PAR-2
  • Receptors, Thrombin / immunology*
  • Receptors, Thrombin / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Trinitrobenzenesulfonic Acid / adverse effects

Substances

  • Hyaluronan Receptors
  • Interleukin-2
  • Oligopeptides
  • Peptide Fragments
  • Receptor, PAR-2
  • Receptors, Thrombin
  • seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide
  • calcitonin gene-related peptide (8-37)
  • Interleukin-12
  • Interferon-gamma
  • Trinitrobenzenesulfonic Acid
  • Calcitonin Gene-Related Peptide
  • Capsaicin