Organic cation transporter 3 modulates murine basophil functions by controlling intracellular histamine levels.
In this study, we identify the bidirectional organic cation transporter 3 (OCT3/Slc22a3) as the molecule responsible for histamine uptake by murine basophils. We demonstrate that OCT3 participates in the control of basophil functions because exogenous histamine can inhibit its own synthesis--and that of interleukin (IL)-4, IL-6, and IL-13--through this means of transport. Furthermore, ligands of H3/H4 histamine receptors or OCT3 inhibit histamine uptake, and outward transport of newly synthesized histamine. By doing so, they increase the histamine content of basophils, which explains why they mimic the effect of exogenous histamine. These drugs were no longer effective in histamine-free histidine decarboxylase (HDC)-deficient mice, in contrast with histamine itself. Histamine was not taken up and lost its inhibitory effect in mice deficient for OCT3, which proved its specific involvement. Intracellular histamine levels were increased strongly in IL-3-induced OCT3-/- bone marrow basophils, and explained why they generated fewer cytokines than their wild-type counterpart. Their production was enhanced when histamine synthesis was blocked by the specific HDC inhibitor alpha-fluoro-methyl histidine, and underscored the determinant role of histamine in the inhibitory effect. We postulate that pharmacologic modulation of histamine transport might become instrumental in the control of basophil functions during allergic diseases.
Schneider
Elke
E
UMR 8147, Centre National de la Recherche Scientifique, Faculté de Médecine René Descartes, Paris V, Hôpital Necker, 75015 Paris, France. schneider@necker.fr
Machavoine
François
F
Pléau
Jean-Marie
JM
Bertron
Anne-France
AF
Thurmond
Robin L
RL
Ohtsu
Hiroshi
H
Watanabe
Takehiko
T
Schinkel
Alfred H
AH
Dy
Michel
M
D000818:Animals; D001491:Basophils / Q000166:cytology / Q000378:metabolism*; D001693:Biological Transport, Active / Q000235:genetics / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D006632:Histamine / Q000378:metabolism*; D006636:Histamine Release / Q000235:genetics / Q000502:physiology*; D006640:Histidine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D006967:Hypersensitivity / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism; D000099254:Organic Cation Transporter 3
D016207:Cytokines; D006632:Histamine; D006640:Histidine Decarboxylase; D027701:Organic Cation Transport Proteins; D018100:Receptors, Histamine H3; D000099254:Organic Cation Transporter 3