title: Specific leukotriene receptors couple to distinct G proteins to effect stimulation of alveolar macrophage host defense functions.
abstract: Leukotrienes (LTs) are lipid mediators implicated in asthma and other inflammatory diseases. LTB(4) and LTD(4) also participate in antimicrobial defense by stimulating phagocyte functions via ligation of B leukotriene type 1 (BLT1) receptor and cysteinyl LT type 1 (cysLT1) receptor, respectively. Although both Galpha(i) and Galpha(q) proteins have been shown to be coupled to both BLT1 and cysLT1 receptors in transfected cell systems, there is little known about specific G protein subunit coupling to LT receptors, or to other G protein-coupled receptors, in primary cells. In this study we sought to define the role of specific G proteins in pulmonary alveolar macrophage (AM) innate immune responses to LTB(4) and LTD(4). LTB(4) but not LTD(4) reduced cAMP levels in rat AM by a pertussis toxin (PTX)-sensitive mechanism. Enhancement of FcgammaR-mediated phagocytosis and bacterial killing by LTB(4) was also PTX-sensitive, whereas that induced by LTD(4) was not. LTD(4) and LTB(4) induced Ca(2+) and intracellular inositol monophosphate accumulation, respectively, highlighting the role of Galpha(q) protein in mediating PTX-insensitive LTD(4) enhancement of phagocytosis and microbicidal activity. Studies with liposome-delivered G protein blocking Abs indicated a dependency on specific Galpha(q/11) and Galpha(i3) subunits, but not Galpha(i2) or G(beta)gamma, in LTB(4)-enhanced phagocytosis. The selective importance of Galpha(q/11) protein was also demonstrated in LTD(4)-enhanced phagocytosis. The present investigation identifies differences in specific G protein subunit coupling to LT receptors in antimicrobial responses and highlights the importance of defining the specific G proteins coupled to heptahelical receptors in primary cells, rather than simply using heterologous expression systems.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
authors.forename: Camila M
authors.initials: CM
authors.lastname: Peres
authors.forename: David M
authors.initials: DM
authors.lastname: Aronoff
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Serezani
authors.forename: Nicolas
authors.initials: N
authors.lastname: Flamand
authors.forename: Lucia H
authors.initials: LH
authors.lastname: Faccioli
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000096:biosynthesis / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000096:biosynthesis / Q000235:genetics; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D007424:Intracellular Fluid / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000502:physiology; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors / Q000502:physiology; D008262:Macrophage Activation / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018077:Receptors, Leukotriene / Q000378:metabolism* / Q000502:physiology; D014121:Toxoids / Q000494:pharmacology
chemical_list: D018077:Receptors, Leukotriene; D014121:Toxoids; C051093:pertussis toxoid; D007975:Leukotriene B4; D017998:Leukotriene D4; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D051960:GTP-Binding Protein alpha Subunit, Gi2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11