O'Flaherty J T, Cordes J F, Lee S L, Samuel M, Thomas M J
Department of Medicine, Wake Forest University Medical Center, Winston-Salem, NC.
Biochim Biophys Acta. 1994 Dec 15;1201(3):505-15. doi: 10.1016/0304-4165(94)90083-3.
Eicosatetraenoates (ETEs) with 5-oxo residues are known to induce human neutrophil (PMN) Ca2+ transients and chemotaxis. We find that 5-oxoETE, 5-oxo-8-trans-ETE, 5-oxo-15-hydroxy-ETE, 5-hydroxy-ETE, 5-hydroxy-15-oxoETE, 5,15-dioxoETE, and 5,15-dihydroxy-ETE have respective relative potencies of 10, 5, 3, 1, 0.2, 0.1, and 0.02 in: a) causing PMN to mobilize Ca2+, aggregate, and release small amounts of granule enzymes and b) promoting large degranulation and oxidative burst responses in PMN co-challenged with platelet-activating factor, tumor necrosis factor-alpha, or ATP. Contrastingly, 12(R)-hydroxy-ETE, 12(S)-hydroxy-ETE, and 12-oxoETE induced PMN Ca2+ transients and aggregation [respective potencies (5-hydroxy-ETE = 1) of 0.1, 0.01, and 0.003] but did not effect degranulation, and 15-hydroxy-ETE, 15-oxoETE, and 15-oxo-11-trans-ETE were inactive in all assays. Finally, 5-oxo/hydroxy-ETEs desensitized PMN to themselves but not to 12-oxo/hydroxy-ETEs or leukotriene (LT)B4; 12-oxo/hydroxy-ETEs and LTB4 desensitized PMN to themselves and each other but not to 5-oxo/hydroxy-ETEs; 15-oxo/hydroxy-ETEs did not desensitize PMN; and a LTB4 receptor antagonist blocked responses to LTB4 and 12-oxo/hydroxy-ETEs but not to 5-oxo/hydroxy-ETEs. Thus, 5-oxo/hydroxy-ETEs act by a common, LTB4 receptor-independent mechanism that recognizes 5- but not 12- or 15-oxo/hydroxy-ETEs and prefers oxo over hydroxy residues at C5 whereas 12-oxo/hydroxy-ETEs act via a LTB4 receptor mechanism that recognizes 12- but not 5- or 15-oxo/hydroxy-ETEs and prefers hydroxy over oxo residues at C12.
已知带有5-氧代残基的二十碳四烯酸酯（ETEs）可诱导人类中性粒细胞（PMN）的Ca2+瞬变和趋化作用。我们发现，5-氧代ETE、5-氧代-8-反式-ETE、5-氧代-15-羟基-ETE、5-羟基-ETE、5-羟基-15-氧代ETE、5,15-二氧代ETE和5,15-二羟基-ETE在以下方面具有各自相对效力：10、5、3、1、0.2、0.1和0.02，a）使PMN动员Ca2+、聚集并释放少量颗粒酶，以及b）在与血小板活化因子、肿瘤坏死因子-α或ATP共同刺激的PMN中促进大量脱颗粒和氧化爆发反应。相比之下，12（R）-羟基-ETE、12（S）-羟基-ETE和12-氧代ETE诱导PMN的Ca2+瞬变和聚集[各自效力（5-羟基-ETE = 1）为0.1、0.01和0.003]，但不影响脱颗粒，并且15-羟基-ETE、15-氧代ETE和15-氧代-11-反式-ETE在所有测定中均无活性。最后，5-氧代/羟基-ETEs使PMN对自身脱敏，但对12-氧代/羟基-ETEs或白三烯（LT）B4不脱敏；12-氧代/羟基-ETEs和LTB4使PMN对自身和彼此脱敏，但对5-氧代/羟基-ETEs不脱敏；15-氧代/羟基-ETEs不使PMN脱敏；并且一种LTB4受体拮抗剂阻断对LTB4和12-氧代/羟基-ETEs的反应，但不阻断对5-氧代/羟基-ETEs的反应。因此，5-氧代/羟基-ETEs通过一种共同的、不依赖LTB4受体的机制起作用，该机制识别5-但不识别12-或15-氧代/羟基-ETEs，并且在C5处优先选择氧代而非羟基残基，而12-氧代/羟基-ETEs通过一种LTB4受体机制起作用，该机制识别12-但不识别5-或15-氧代/羟基-ETEs，并且在C12处优先选择羟基而非氧代残基。
