title: Downregulation of basophil-derived IL-4 and in vivo T(H)2 IgE responses by serotonin and other organic cation transporter 3 ligands.
abstract: BACKGROUND
  Murine basophils can contribute to the T(H)2 polarization of the immune response by providing rapidly large amounts of IL-4, which suggests that pharmacologic downregulation of this cytokine might provide a strategy to attenuate pathologies associated with excessive production.
  
  
  OBJECTIVE
  We examined a number of physiological and pharmacologic ligands of the organic cation transporter 3 (OCT3), a membrane carrier of biogenic amines, for their inhibitory effect on IL-4 production by basophils, selecting the most efficient compounds for in vivo evaluation in basophil-dependent experimental models.
  
  
  METHODS
  IL-4 production by basophils isolated ex vivo or from bone marrow cultures was assessed in response to various stimuli with or without biogenic monoamines or pharmacologic analogs. Selected compounds were administered in vivo to examine their effect on levels of circulating IgE generated during a basophil-dependent T(H)2 response and on basophil activation in mice receiving IL-33.
  
  
  RESULTS
  We found a drastic decrease in IL-4 production by stimulated basophils on exposure to serotonin (5-hydroxytryptamine [5-HT]) that is taken up by basophils through the specific high-affinity transporters serotonin transporter and the polyspecific, high-capacity organic cation transporter 3 (OCT3; or Slc22a3) but inhibits their function exclusively through the latter. This downregulation is likewise observed in vivo in response to 5-HT and other OCT3 ligands, as well as in human basophils sorted from PMBCs of nonatopic donors.
  
  
  CONCLUSIONS
  We provide evidence for a new means of downregulating IL-4 production by basophils, both in vitro and in vivo, through OCT3 targeted by 5-HT and pharmacologic ligands.
authors.affiliation: Université Paris Descartes, Faculté de Médecine, CNRS UMR 8147 Cytokines, Hematopoiesis and Immune Response, Hôpital Necker, Paris, France. elke.schneider@parisdescartes.fr
authors.forename: Elke
authors.initials: E
authors.lastname: Schneider
authors.forename: François
authors.initials: F
authors.lastname: Machavoine
authors.forename: Rachel
authors.initials: R
authors.lastname: Bricard-Rignault
authors.forename: Mélanie
authors.initials: M
authors.lastname: Levasseur
authors.forename: Anne France
authors.initials: AF
authors.lastname: Petit-Bertron
authors.forename: Sophie
authors.initials: S
authors.lastname: Gautron
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Ribeil
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.forename: Salah
authors.initials: S
authors.lastname: Mecheri
authors.forename: Francine
authors.initials: F
authors.lastname: Côté
authors.forename: Michel
authors.initials: M
authors.lastname: Dy
mesh_terms: D000818:Animals; D001491:Basophils / Q000276:immunology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology* / Q000378:metabolism; D000067596:Interleukin-33; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000819:agonists* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012701:Serotonin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D000099254:Organic Cation Transporter 3
chemical_list: D007073:Immunoglobulin E; D000067596:Interleukin-33; D015847:Interleukin-4; D007378:Interleukins; D008024:Ligands; D027701:Organic Cation Transport Proteins; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D000099254:Organic Cation Transporter 3; C506536:IL33 protein, human; C508598:IL4 protein, human