Cytochrome P-4504F18 is the leukotriene B4 ω-1/ω-2 hydroxylase in mouse polymorphonuclear leukocytes -: Identification as the functional orthologue of human polymorphonuclear leukocyte CYP4F3A in the down-regulation of responses to LTB4
Cytochrome P-4504F18 is the leukotriene B4 ω-1/ω-2 hydroxylase in mouse polymorphonuclear leukocytes -: Identification as the functional orthologue of human polymorphonuclear leukocyte CYP4F3A in the down-regulation of responses to LTB4
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DOI：
10.1074/jbc.m513101200
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发表时间：
2006-03-17
影响因子：
4.8
通讯作者：
Soberman, RJ
中科院分区：
文献类型：
--
作者：
Christmas, P;Tolentino, K;Soberman, RJ
白三烯B-4（LTB 4）是一种对多形核白细胞（PMN）和其它细胞有吸引力的化学物质。通过细胞色素P-450（CYP）4F 3A催化的ω-氧化作用，人PMN活化LTB 4。CYP 4Fs对LTB 4的酶失活对下调细胞对LTB 4的功能反应的贡献尚不清楚。为了阐明CYP 4F介导的LTB 4失活在终止PMN对LTB 4的反应中的作用，并确定未来小鼠遗传学研究的靶点，我们确定了在小鼠骨髓细胞中催化LTB 4的omega-1和omega-2氧化的酶为CYP 4F 18。如通过质谱法测定的，该酶催化LTB 4转化为19-OH LTB 4，并且在较小程度上催化18-OH LTB 4。CYP 4F 18的抑制导致钙通量显著增加，小鼠PMN对LTB 4的趋化反应增加220%。CYP 4F 18的表达诱导骨髓来源的树突状细胞的细菌脂多糖，TLR 4的配体，和聚（I中心点C），TLR 3的配体。然而，当骨髓来源的髓样树突状细胞从爪垫运输到腘淋巴结时，CYP 4F 18的表达下调。结果表明，CYP 4F 18是调节小鼠PMN中LTB 4代谢和功能反应的关键蛋白，并将其鉴定为人PMN CYP 4F 3A的功能直向同源物。
Leukotriene B-4 (LTB4) is a potent chemoattractant for polymorphonuclear leukocytes (PMN) and other cells. Human PMN inactivate LTB4 by omega-oxidation catalyzed by cytochrome P-450 (CYP) 4F3A. The contribution of the enzymatic inactivation of LTB4 by CYP4Fs to down-regulating functional responses of cells to LTB4 is unknown. To elucidate the role of CYP4F-mediated inactivation of LTB4 in terminating the responses of PMN to LTB4 and to identify a target for future genetic studies in mice, we have identified the enzyme that catalyzes the omega-1 and omega-2 oxidation of LTB4 in mouse myeloid cells as CYP4F18. As determined by mass spectrometry, this enzyme catalyzes the conversion of LTB4 to 19-OH LTB4 and to a lesser extent 18-OH LTB4. Inhibition of CYP4F18 resulted in a marked increase in calcium flux and a 220% increase in the chemotactic response of mouse PMN to LTB4. CYP4F18 expression was induced in bone marrow-derived dendritic cells by bacterial lipopolysaccharide, a ligand for TLR4, and by poly( I center dot C), a ligand for TLR3. However, when bone marrow-derived myeloid dendritic cells trafficked to popliteal lymph nodes from paw pads, the expression of CYP4F18 was down-regulated. The results identify CYP4F18 as a critical protein in the regulation of LTB4 metabolism and functional responses in mouse PMN and identify it as the functional orthologue of human PMN CYP4F3A.