The Journal of Experimental Medicine
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Published 1 August 2005. doi:10.1084/jem.20050195
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 3, 387-393
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BRIEF DEFINITIVE REPORT

 Organic cation transporter 3 modulates murine basophil functions by controlling intracellular histamine levels

Elke Schneider1, François Machavoine1, Jean-Marie Pléau1, Anne-France Bertron1, Robin L. Thurmond2, Hiroshi Ohtsu3, Takehiko Watanabe3, Alfred H. Schinkel4, and Michel Dy1

1 UMR 8147, Centre National de la Recherche Scientifique (CNRS), Faculté de Médecine René Descartes, Paris V, Hôpital Necker, 75015 Paris, France
2 Johnson & Johnson Pharmaceutical Research and Development, L.L.C., San Diego, CA 92121
3 Tohoku University Graduate School of Engineering, Sendai 980-8579, Japan
4 Netherlands Cancer Institute, Division of Experimental Therapy, 1066 CX Amsterdam, Netherlands

CORRESPONDENCE Elke Schneider: schneider{at}necker.fr

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.


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