Activation of the Prostaglandin D2 Receptor DP2/CRTH2 Increases Allergic Inflammation in Mouse 1

Allergic pathologies are often associated with IgE production, mast cell activation, and eosinophilia. PGD2 is the major eicosanoid, among several inflammatory mediators, released by mast cells. PGD2 binds to two membrane receptors, D prostanoid receptor (DP)1 and DP2, endowed with antagonistic properties. In humans, DP2 is preferentially expressed on type 2 lymphocytes, eosinophils, and basophils and mediates chemotaxis in vitro. Although not yet supported by in vivo studies, DP2 is thought to be important in the promotion of Th2-related inflammation. Herein, we demonstrate that mouse eosinophils express both DP1 and DP2 and that PGD2 exerts in vitro chemotactic effects on eosinophils through DP2 activation. Furthermore, 13,14-dihydro-15-keto-PGD2, a specific DP2 agonist not only increases eosinophil recruitment at inflammatory sites but also the pathology in two in vivo models of allergic inflammation: atopic dermatitis and allergic asthma. By contrast, DP1 activation tends to ameliorate the pathology in asthma. Taken together, these results support the hypothesis that DP2 might play a critical role in allergic diseases and underline the interest of DP2 antagonists in human therapy.

[1]  S. Orkin,et al.  A Critical Role for Eosinophils in Allergic Airways Remodeling , 2004, Science.

[2]  E. Lenkiewicz,et al.  Defining a Link with Asthma in Mice Congenitally Deficient in Eosinophils , 2004, Science.

[3]  Masataka Nakamura,et al.  Effects of prostaglandin D2 on helper T cell functions. , 2004, Biochemical and biophysical research communications.

[4]  H. Hammad,et al.  Activation of the D Prostanoid Receptor 1 Regulates Immune and Skin Allergic Responses1 , 2004, The Journal of Immunology.

[5]  M. Hatano,et al.  Prostaglandin D2 Reinforces Th2 Type Inflammatory Responses of Airways to Low-dose Antigen through Bronchial Expression of Macrophage-derived Chemokine , 2003, The Journal of experimental medicine.

[6]  K. Sugamura,et al.  Gene structure and functional properties of mouse CRTH2, a prostaglandin D2 receptor. , 2003, Biochemical and biophysical research communications.

[7]  J. Auwerx,et al.  Peroxisome Proliferator–activated Receptors α and γ Down-regulate Allergic Inflammation and Eosinophil Activation , 2003, The Journal of experimental medicine.

[8]  R. Breyer,et al.  Expression and Molecular Pharmacology of the Mouse CRTH2 Receptor , 2003, Journal of Pharmacology and Experimental Therapeutics.

[9]  M. Pichavant,et al.  Prostaglandin D2 Affects the Maturation of Human Monocyte-Derived Dendritic Cells: Consequence on the Polarization of Naive Th Cells1 , 2003, The Journal of Immunology.

[10]  A. Hartnell,et al.  Δ12-Prostaglandin J2, a Plasma Metabolite of Prostaglandin D2, Causes Eosinophil Mobilization from the Bone Marrow and Primes Eosinophils for Chemotaxis1 , 2003, The Journal of Immunology.

[11]  S. Narumiya,et al.  Prostaglandin D2 inhibits the production of interleukin‐12 in murine dendritic cells through multiple signaling pathways , 2003, European journal of immunology.

[12]  F. Gantner,et al.  An Orally Bioavailable Small Molecule Antagonist of CRTH2, Ramatroban (BAY u3405), Inhibits Prostaglandin D2-Induced Eosinophil Migration in Vitro , 2003, Journal of Pharmacology and Experimental Therapeutics.

[13]  J. Rokach,et al.  15R-Methyl-Prostaglandin D2 Is a Potent and Selective CRTH2/DP2 Receptor Agonist in Human Eosinophils , 2003, Journal of Pharmacology and Experimental Therapeutics.

[14]  Z. Ikezawa,et al.  Association of a new-type prostaglandin D2 receptor CRTH2 with circulating T helper 2 cells in patients with atopic dermatitis. , 2002, The Journal of investigative dermatology.

[15]  Min Zhang,et al.  IgE-Dependent Mast Cell Activation Potentiates Airway Responses in Murine Asthma Models1 , 2002, The Journal of Immunology.

[16]  Masataka Nakamura,et al.  Cutting Edge: Agonistic Effect of Indomethacin on a Prostaglandin D2 Receptor, CRTH2 , 2002, The Journal of Immunology.

[17]  M. Sakai,et al.  Accumulation of CRTH2-positive T-helper 2 and T-cytotoxic 2 cells at implantation sites of human decidua in a prostaglandin D(2)-mediated manner. , 2002, Molecular human reproduction.

[18]  Yoshihiro Urade,et al.  Pronounced Eosinophilic Lung Inflammation and Th2 Cytokine Release in Human Lipocalin-Type Prostaglandin D Synthase Transgenic Mice1 , 2002, The Journal of Immunology.

[19]  R. Geha,et al.  Mast cells regulate IFN-gamma expression in the skin and circulating IgE levels in allergen-induced skin inflammation. , 2002, The Journal of allergy and clinical immunology.

[20]  G. O'neill,et al.  Selective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD2 receptors CRTH2 and DP. , 2001, The Journal of allergy and clinical immunology.

[21]  K. Yasui,et al.  Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751. , 2001, The Journal of pharmacology and experimental therapeutics.

[22]  D. Dombrowicz,et al.  Human Eosinophils and Human High Affinity IgE Receptor Transgenic Mouse Eosinophils Express Low Levels of High Affinity IgE Receptor, but Release IL-10 upon Receptor Activation , 2001, The Journal of Immunology.

[23]  A. Capron,et al.  Role of the Parasite-Derived Prostaglandin D2 in the Inhibition of Epidermal Langerhans Cell Migration during Schistosomiasis Infection , 2001, The Journal of experimental medicine.

[24]  P. Hart.  Regulation of the inflammatory response in asthma by mast cell products , 2001, Immunology and cell biology.

[25]  K. Sugamura,et al.  Prostaglandin D2 Selectively Induces Chemotaxis in T Helper Type 2 Cells, Eosinophils, and Basophils via Seven-Transmembrane Receptor Crth2 , 2001, The Journal of experimental medicine.

[26]  S. Narumiya,et al.  Prostaglandin D2 as a mediator of allergic asthma. , 2000, Science.

[27]  L. Cosmi,et al.  CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease. , 2000, European journal of immunology.

[28]  K. Sugamura,et al.  CRTH2, an orphan receptor of T‐helper‐2‐cells, is expressed on basophils and eosinophils and responds to mast cell‐derived factor(s) , 1999, FEBS letters.

[29]  K. Sugamura,et al.  Molecular cloning, chromosome mapping and characterization of the mouse CRTH2 gene, a putative member of the leukocyte chemoattractant receptor family. , 1999, Gene.

[30]  R. Geha,et al.  Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. , 1998, The Journal of clinical investigation.

[31]  E. Gelfand,et al.  Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. , 1997, American journal of respiratory and critical care medicine.

[32]  S. Galli,et al.  Absence of Fc epsilonRI alpha chain results in upregulation of Fc gammaRIII-dependent mast cell degranulation and anaphylaxis. Evidence of competition between Fc epsilonRI and Fc gammaRIII for limiting amounts of FcR beta and gamma chains. , 1997, The Journal of clinical investigation.

[33]  E. Schulman,et al.  Mast cell mediators prostaglandin-D2 and histamine activate human eosinophils. , 1992, Journal of immunology.

[34]  J. Miyazaki,et al.  Transgenic mice expressing a B cell growth and differentiation factor gene (interleukin 5) develop eosinophilia and autoantibody production , 1991, The Journal of experimental medicine.

[35]  M. Strath,et al.  Eosinophilia in transgenic mice expressing interleukin 5 , 1990, The Journal of experimental medicine.

[36]  J. Nadel,et al.  Prostaglandin D2 causes accumulation of eosinophils in the lumen of the dog trachea. , 1989, Journal of applied physiology.

[37]  J. Murray,et al.  Release of prostaglandin D2 into human airways during acute antigen challenge. , 1986, The New England journal of medicine.

[38]  S. Holgate,et al.  The bronchoconstrictor effect of inhaled prostaglandin D2 in normal and asthmatic men. , 1984, The New England journal of medicine.