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

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.

• Authors: S Fiorucci, A Mencarelli, B Palazzetti, E Distrutti, N Vergnolle, M D Hollenberg, J L Wallace, A Morelli, G Cirino
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 98 Issue 24 Pg. 13936-41 (Nov 20 2001) ISSN: 0027-8424 [Print] United States
• PMID: 11717450 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• Animals
• Calcitonin Gene-Related Peptide (pharmacology)
• Capsaicin (pharmacology)
• Cells, Cultured
• Colitis (chemically induced, immunology, pathology, prevention & control)
• Colon (cytology, 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, metabolism)
• T-Lymphocytes (cytology, drug effects, immunology)
• Trinitrobenzenesulfonic Acid (adverse effects)