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.