title: Opposing roles of prostaglandin D2 receptors in ulcerative colitis.
abstract: Proresolution functions were reported for PGD2 in colitis, but the role of its two receptors, D-type prostanoid (DP) and, in particular, chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), is less well defined. We investigated DP and CRTH2 expression and function during human and murine ulcerative colitis (UC). Expression of receptors was measured by flow cytometry on peripheral blood leukocytes and by immunohistochemistry and immunoblotting in colon biopsies of patients with active UC and healthy individuals. Receptor involvement in UC was evaluated in a mouse model of dextran sulfate sodium colitis. DP and CRTH2 expression changed in leukocytes of patients with active UC in a differential manner. In UC patients, DP showed higher expression in neutrophils but lower in monocytes as compared with control subjects. In contrast, CRTH2 was decreased in eosinophils, NK, and CD3(+) T cells but not in monocytes and CD3(+)/CD4(+) T cells. The decrease of CRTH2 on blood eosinophils clearly correlated with disease activity. DP correlated positively with disease activity in eosinophils but inversely in neutrophils. CRTH2 internalized upon treatment with PGD2 and 11-dehydro TXB2 in eosinophils of controls. Biopsies of UC patients revealed an increase of CRTH2-positive cells in the colonic mucosa and high CRTH2 protein content. The CRTH2 antagonist CAY10595 improved, whereas the DP antagonist MK0524 worsened inflammation in murine colitis. DP and CRTH2 play differential roles in UC. Although expression of CRTH2 on blood leukocytes is downregulated in UC, CRTH2 is present in colon tissue, where it may contribute to inflammation, whereas DP most likely promotes anti-inflammatory actions.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Eva M
authors.initials: EM
authors.lastname: Sturm
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Balazs
authors.initials: B
authors.lastname: Radnai
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Katharina
authors.initials: K
authors.lastname: Jandl
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Angela
authors.initials: A
authors.lastname: Stančić
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Parzmair
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Christoph
authors.initials: C
authors.lastname: Högenauer
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Patrizia
authors.initials: P
authors.lastname: Kump
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Heimo
authors.initials: H
authors.lastname: Wenzl
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Petritsch
authors.affiliation: Division of Endocrinology and Metabolic Diseases, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria; and.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Rufina
authors.initials: R
authors.lastname: Schuligoi
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
authors.affiliation: Institute of Clinical Pharmacology, Goethe University, 60590 Frankfurt/Main, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria;
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria; rudolf.schicho@medunigraz.at.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schicho
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D017252:CD3 Complex / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D015230:Prostaglandin D2 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D055815:Young Adult
chemical_list: D017252:CD3 Complex; D007211:Indoles; C518174:MK-0524; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D016264:Dextran Sulfate; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor