Downregulation of basophil-derived IL-4 andin vivoTH2 IgE responses by serotonin and other organic cation transporter 3 ligands

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 forin vivoevaluation in basophil-dependent experimental models. Methods IL-4 production by basophils isolatedex vivoor from bone marrow cultures was assessed in response to various stimuli with or without biogenic monoamines or pharmacologic analogs. Selected compounds were administeredin vivoto 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 observedin vivoin 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, bothin vitroandin vivo, through OCT3 targeted by 5-HT and pharmacologic ligands.