title: Activated prostaglandin D2 receptors on macrophages enhance neutrophil recruitment into the lung.
abstract: BACKGROUND
  Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor-homologous molecule expressed on T(H)2 cells) in regulating macrophages have not been elucidated to date.
  
  
  OBJECTIVE
  We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo.
  
  
  METHODS
  In vitro studies, including migration, Ca(2+) flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice.
  
  
  RESULTS
  Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca(2+) flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD2 receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD2-enhanced inflammatory response. Activation of PGD2 receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD2 synthesis.
  
  
  CONCLUSIONS
  For the first time, our results show that PGD2 markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation.
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 Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Elvira
authors.initials: E
authors.lastname: Stacher
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Bálint
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Sturm
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Jovana
authors.initials: J
authors.lastname: Maric
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Miriam
authors.initials: M
authors.lastname: Peinhaupt
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Luschnig
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria; Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Ida
authors.initials: I
authors.lastname: Aringer
authors.affiliation: Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Stockholm, Sweden.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fauland
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria; Center for Infectious Medicine, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Konya
authors.affiliation: Institute of Environmental Medicine, Experimental Asthma and Allergy Research Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Dahlen
authors.affiliation: Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Stockholm, Sweden.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
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: Rufina
authors.initials: R
authors.lastname: Schuligoi
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria. Electronic address: akos.heinemann@medunigraz.at.
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004731:Endotoxins / Q000009:adverse effects / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D055370:Lung Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015230:Prostaglandin D2 / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D004731:Endotoxins; D018836:Inflammation Mediators; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D014409:Tumor Necrosis Factor-alpha; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor
keywords: D-type prostanoid receptor 1; D-type prostanoid receptor 2/chemoattractant receptor–homologous molecule expressed on T(H)2 cells; hematopoietic prostaglandin D synthase; macrophages; neutrophils; prostaglandin D(2); pulmonary inflammation