The Journal of Experimental Medicine
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Published online March 31, 2008
doi:10.1084/jem.20072329
The Journal of Experimental Medicine, Vol. 205, No. 4, 759-766
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Okuno et al.
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BRIEF DEFINITIVE REPORT

 12(S)-hydroxyheptadeca-5Z, 8E, 10E–trienoic acid is a natural ligand for leukotriene B4 receptor 2

Toshiaki Okuno1,2,3, Yoshiko Iizuka1, Hiroshi Okazaki3, Takehiko Yokomizo1,3,4, Ryo Taguchi2,4, and Takao Shimizu1

1 Department of Biochemistry and Molecular Biology and 2 Department of Metabolome, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
3 Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
4 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-8613, Japan

CORRESPONDENCE Takao Shimizu: tshimizu{at}m.u-tokyo.ac.jp

Activated blood platelets and macrophages metabolize prostaglandin H2 into thromboxane A2 and 12(S)-hydroxyheptadeca-5Z, 8E, 10E–trienoic acid (12-HHT) in an equimolar ratio through the action of thromboxane synthase. Although it has been shown that 12-HHT is abundant in tissues and bodily fluids, this compound has long been viewed as a by-product lacking any specific function. We show that 12-HHT is a natural ligand for leukotriene B4 (LTB4) receptor-2 (BLT2), a G protein–coupled receptor that was originally identified as a low-affinity receptor for LTB4. BLT2 agonistic activity in lipid fractions from rat small intestine was identified as 12-HHT using high-performance liquid chromatography and mass spectrometry. Exogenously expressed BLT2 in mammalian cells was activated by synthetic 12-HHT, as assessed by guanosine 5'-O-(3-thio) triphosphate binding, the activation of intracellular signaling pathways, and chemotaxis assay. Displacement analysis using [3H]LTB4 showed that 12-HHT binds to BLT2 with a higher affinity than LTB4. Lipid extracts from cyclooxygenase 1–deficient mice failed to activate BLT2. Bone marrow–derived mast cells (BMMCs) isolated from wild-type mice migrated toward a low concentration of 12-HHT, whereas BMMCs from BLT2-deficient mice did not. We conclude that 12-HHT is a natural lipid agonist of BLT2 in vivo and induces chemotaxis of mast cells.


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