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

T Okuno, Y Iizuka, H Okazaki, T Yokomizo… - The Journal of …, 2008 - rupress.org
T Okuno, Y Iizuka, H Okazaki, T Yokomizo, R Taguchi, T Shimizu
The Journal of experimental medicine, 2008rupress.org
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 …
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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