title: Eosinophils Contribute to Intestinal Inflammation via Chemoattractant Receptor-homologous Molecule Expressed on Th2 Cells, CRTH2, in Experimental Crohn's Disease.
abstract: OBJECTIVE
  Prostaglandin [PG] D2 activates two receptors, DP and CRTH2. Antagonism of CRTH2 has been shown to promote anti-allergic and anti-inflammatory effects. We investigated whether CRTH2 may play a role in Crohn's disease [CD], focusing on eosinophils which are widely present in the inflamed mucosa of CD patients and express both receptors.
  
  
  METHODS
  Using the 2,4,6-trinitrobenzenesulfonic acid [TNBS]-induced colitis model, involvement of CRTH2 in colitis was investigated by pharmacological antagonism, immunohistochemistry, Western blotting, immunoassay, and leukocyte recruitment. Chemotactic assays were performed with isolated human eosinophils. Biopsies and serum samples of CD patients were examined for presence of CRTH2 and ligands, respectively.
  
  
  RESULTS
  High amounts of CRTH2-positive cells, including eosinophils, are present in the colonic mucosa of mice with TNBS colitis and in human CD. The CRTH2 antagonist OC-459, but not the DP antagonist MK0524, reduced inflammation scores and decreased TNF-α, IL-1β, and IL-6 as compared with control mice. OC-459 inhibited recruitment of eosinophils into the colon and also inhibited CRTH2-induced chemotaxis of human eosinophils in vitro. Eosinophil-depleted ΔdblGATA knockout mice were less sensitive to TNBS-induced colitis, whereas IL-5 transgenic mice with lifelong eosinophilia were more severely affected than wild types. In addition, we show that serum levels of PGD2 and Δ(12)-PGJ2 were increased in CD patients as compared with control individuals.
  
  
  CONCLUSIONS
  CRTH2 plays a pro-inflammatory role in TNBS-induced colitis. Eosinophils contribute to the severity of the inflammation, which is improved by a selective CRTH2 antagonist. CRTH2 may, therefore, represent an important target in the pharmacotherapy of CD.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Balázs
authors.initials: B
authors.lastname: Radnai
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Sturm
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Angela
authors.initials: A
authors.lastname: Stančić
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Jandl
authors.affiliation: Institute of Clinical Pharmacology, Goethe University, Frankfurt/Main, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Labocha
authors.affiliation: Institute of Clinical Pharmacology, Goethe University, Frankfurt/Main, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Grill
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Carina
authors.initials: C
authors.lastname: Hasenoehrl
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Gregor
authors.initials: G
authors.lastname: Gorkiewicz
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Ákos
authors.initials: Á
authors.lastname: Heinemann
authors.affiliation: Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Högenauer
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria rudolf.schicho@medunigraz.at.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schicho
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D003106:Colon / Q000276:immunology* / Q000378:metabolism; D003424:Crohn Disease / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004804:Eosinophils / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007118:Immunoassay; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D015415:Biomarkers; D016207:Cytokines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D014302:Trinitrobenzenesulfonic Acid; C036293:prostaglandin D2 receptor
keywords: CRTH2; Crohn′s disease; eosinophils