title: Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation.
abstract: PGD(2) is a key mediator of allergic inflammatory diseases that is mainly synthesized by mast cells, which constitutively express high levels of the terminal enzyme involved in PGD(2) synthesis, the hematopoietic PGD synthase (H-PGDS). In this study, we investigated whether eosinophils are also able to synthesize, and therefore, supply biologically active PGD(2). PGD(2) synthesis was evaluated within human blood eosinophils, in vitro differentiated mouse eosinophils, and eosinophils infiltrating inflammatory site of mouse allergic reaction. Biological function of eosinophil-derived PGD(2) was studied by employing inhibitors of synthesis and activity. Constitutive expression of H-PGDS was found within nonstimulated human circulating eosinophils. Acute stimulation of human eosinophils with A23187 (0.1-5 μM) evoked PGD(2) synthesis, which was located at the nuclear envelope and was inhibited by pretreatment with HQL-79 (10 μM), a specific H-PGDS inhibitor. Prestimulation of human eosinophils with arachidonic acid (10 μM) or human eotaxin (6 nM) also enhanced HQL-79-sensitive PGD(2) synthesis, which, by acting on membrane-expressed specific receptors (D prostanoid receptors 1 and 2), displayed an autocrine/paracrine ability to trigger leukotriene C(4) synthesis and lipid body biogenesis, hallmark events of eosinophil activation. In vitro differentiated mouse eosinophils also synthesized paracrine/autocrine active PGD(2) in response to arachidonic acid stimulation. In vivo, at late time point of the allergic reaction, infiltrating eosinophils found at the inflammatory site appeared as an auxiliary PGD(2)-synthesizing cell population. Our findings reveal that eosinophils are indeed able to synthesize and secrete PGD(2), hence representing during allergic inflammation an extra cell source of PGD(2), which functions as an autocrine signal for eosinophil activation.
authors.affiliation: Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Luna-Gomes
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Magalhães
authors.forename: Fabio P
authors.initials: FP
authors.lastname: Mesquita-Santos
authors.forename: Ilka
authors.initials: I
authors.lastname: Bakker-Abreu
authors.forename: Rafaela F
authors.initials: RF
authors.lastname: Samico
authors.forename: Raphael
authors.initials: R
authors.lastname: Molinaro
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Calheiros
authors.forename: Bruno L
authors.initials: BL
authors.lastname: Diaz
authors.forename: Patrícia T
authors.initials: PT
authors.lastname: Bozza
authors.forename: Peter F
authors.initials: PF
authors.lastname: Weller
authors.forename: Christianne
authors.initials: C
authors.lastname: Bandeira-Melo
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000276:immunology*; D002384:Catalysis; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006410:Hematopoiesis / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000473:pathology; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000097:blood; D054834:Lipocalins / Q000096:biosynthesis / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019899:Paracrine Communication / Q000276:immunology; D015230:Prostaglandin D2 / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D011971:Receptors, Immunologic / Q000097:blood / Q000502:physiology; D011982:Receptors, Prostaglandin / Q000097:blood / Q000502:physiology
chemical_list: D054834:Lipocalins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor
references.citation: FEBS Lett. 2006 Jan 23;580(2):373-9
references.pmid: 16378605
references.citation: Arch Otolaryngol Head Neck Surg. 2007 Jul;133(7):693-700
references.pmid: 17638783
references.citation: J Immunol. 2008 Sep 15;181(6):4004-9
references.pmid: 18768855
references.citation: Biochim Biophys Acta. 2009 Mar;1791(3):156-65
references.pmid: 19367763
references.citation: Am J Respir Cell Mol Biol. 2005 Sep;33(3):254-61
references.pmid: 15947420
references.citation: Thorax. 2004 Jun;59(6):453-5
references.pmid: 15170020
references.citation: J Immunol. 1988 Oct 1;141(7):2413-9
references.pmid: 3139758
references.citation: Am J Respir Crit Care Med. 2011 Feb 1;183(3):299-309
references.pmid: 20813890
references.citation: N Engl J Med. 1986 Sep 25;315(13):800-4
references.pmid: 3462506
references.citation: Br J Pharmacol. 2002 Dec;137(8):1163-72
references.pmid: 12466225
references.citation: J Immunol. 2000 Mar 1;164(5):2277-80
references.pmid: 10679060
references.citation: Br J Pharmacol. 2011 Apr;162(8):1674-85
references.pmid: 20973774
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2003 Aug-Sep;69(2-3):187-94
references.pmid: 12895602
references.citation: Am J Pathol. 2010 Jan;176(1):227-37
references.pmid: 20008150
references.citation: Am J Rhinol. 2006 May-Jun;20(3):342-8
references.pmid: 16871941
references.citation: J Immunol. 2006 Feb 1;176(3):1326-30
references.pmid: 16424158
references.citation: J Biol Chem. 1995 Aug 11;270(32):18910-6
references.pmid: 7642548
references.citation: Am J Pathol. 2011 Aug;179(2):775-82
references.pmid: 21712025
references.citation: J Immunol Methods. 2011 Jun 30;369(1-2):91-7
references.pmid: 21565196
references.citation: J Allergy Clin Immunol. 1980 Apr;65(4):269-73
references.pmid: 6766962
references.citation: FEBS Lett. 1999 Oct 8;459(2):195-9
references.pmid: 10518017
references.citation: Am J Respir Cell Mol Biol. 2011 Apr;44(4):509-16
references.pmid: 20539011
references.citation: Pharmacol Ther. 2007 Jan;113(1):30-49
references.pmid: 16945418
references.citation: Prostaglandins Other Lipid Mediat. 2004 Jan;73(1-2):87-101
references.pmid: 15165034
references.citation: J Allergy Clin Immunol. 2009 Nov;124(5):942-8.e1-9
references.pmid: 19748656
references.citation: Prostaglandins Other Lipid Mediat. 2005 Jan;75(1-4):153-67
references.pmid: 15789622
references.citation: J Allergy Clin Immunol. 2002 Mar;109(3):393-400
references.pmid: 11897981
references.citation: J Biol Chem. 1999 May 28;274(22):15719-24
references.pmid: 10336471
references.citation: Pharmacology. 2010;85(6):372-82
references.pmid: 20559016
references.citation: Circ Res. 2000 May 12;86(9):967-73
references.pmid: 10807869
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2003 Aug-Sep;69(2-3):163-7
references.pmid: 12895599
references.citation: J Immunol. 2007 Aug 15;179(4):2565-75
references.pmid: 17675519
references.citation: J Allergy Clin Immunol. 2006 Oct;118(4):789-98; quiz 799-800
references.pmid: 17030228
references.citation: Immunity. 2009 Sep 18;31(3):425-37
references.pmid: 19766085
references.citation: Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11192-6
references.pmid: 7972033
references.citation: J Immunol. 2002 Apr 1;168(7):3563-9
references.pmid: 11907120
references.citation: J Biol Chem. 2004 Feb 27;279(9):7663-70
references.pmid: 14668348
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2003 Aug-Sep;69(2-3):195-205
references.pmid: 12895603
references.citation: Am Rev Respir Dis. 1983 Oct;128(4):597-602
references.pmid: 6354022
references.citation: Steroids. 2008 Oct;73(11):1148-59
references.pmid: 18555503
references.citation: J Exp Med. 2002 Sep 16;196(6):841-50
references.pmid: 12235216
references.citation: Korean J Intern Med. 2011 Mar;26(1):8-18
references.pmid: 21437156
references.citation: J Immunol. 1982 Oct;129(4):1627-31
references.pmid: 6809826
references.citation: J Immunol. 1991 Jan 15;146(2):671-6
references.pmid: 1702812
references.citation: Blood. 2001 Sep 15;98(6):1942-8
references.pmid: 11535533
references.citation: J Allergy Clin Immunol. 2009 Sep;124(3):417-21
references.pmid: 19482346
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11091-6
references.pmid: 8855314
references.citation: J Allergy Clin Immunol. 1996 Aug;98(2):421-32
references.pmid: 8757220
references.citation: J Allergy Clin Immunol. 2003 Apr;111(4):743-9
references.pmid: 12704352
references.citation: Methods Mol Biol. 2011;689:163-81
references.pmid: 21153792
references.citation: Biochim Biophys Acta. 1976 Apr 22;431(1):189-83
references.pmid: 1268242
references.citation: J Biol Chem. 2011 Aug 5;286(31):27471-82
references.pmid: 21669866
references.citation: N Engl J Med. 1984 Jul 26;311(4):209-13
references.pmid: 6588293
references.citation: J Immunol. 2003 May 1;170(9):4752-8
references.pmid: 12707356
references.citation: Nature. 1996 Nov 7;384(6604):39-43
references.pmid: 8900274
references.citation: J Biol Chem. 2001 Jun 22;276(25):22779-87
references.pmid: 11274187
references.citation: J Exp Med. 2001 Jan 15;193(2):255-61
references.pmid: 11208866