Downregulation of basophil-derived IL-4 and in vivo TH2 IgE responses by serotonin and other organic cation transporter 3 ligands - 30/09/11
, François Machavoine, MSc a, Rachel Bricard-Rignault, MSc a, Mélanie Levasseur, MSc a, Anne France Petit-Bertron, PhD a, Sophie Gautron, PhD b, Jean-Antoine Ribeil, MD, PhD a, Jean-Marie Launay, MD, PhD c, Salah Mecheri, PhD d, Francine Côté, PhD a, Michel Dy, PhD a
Corresponding author: Elke Schneider, PhD, CNRS UMR 8147, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France.Abstract |
Background |
Murine basophils can contribute to the TH2 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 TH2 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.
El texto completo de este artículo está disponible en PDF.Key words : Basophils, IL-4, TH2-type immune response, organic cation transporter 3
Abbreviations used : 5-HT, BMC, BMDB, CYP450, Dat, DNP, Gapdh, HDC, Net, OCT3, SERT
Esquema
| Supported by the CNRS, Université Paris Descartes, and a grant from the “Agence National pour la Recherche” (ANR 05-BLAN-0155-01). |
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| Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. |
Vol 128 - N° 4
P. 864 - octobre 2011 Regresar al número
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