Contributions of the three CYP1 monooxygenases to pro-inflammatory and inflammation-resolution lipid mediator pathways.
Contributions of the three CYP1 monooxygenases to pro-inflammatory and inflammation-resolution lipid mediator pathways.
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DOI：
10.4049/jimmunol.1300699
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发表时间：
2013-09-15
期刊：
影响因子：
--
通讯作者：
Nebert DW
中科院分区：
文献类型：
--
作者：
Divanovic S;Dalli J;Jorge-Nebert LF;Flick LM;Gálvez-Peralta M;Boespflug ND;Stankiewicz TE;Fitzgerald JM;Somarathna M;Karp CL;Serhan CN;Nebert DW
目前，三种细胞色素P450-1单加氧酶都被认为参与了脂质介体的生物合成和/或其局部失活；然而，目前尚不清楚不同的代谢步骤。我们使用多反应监测和基于LC-UV-MS/MS的脂类代谢脂组学来鉴定和定量基础腹膜和酵母多糖刺激的炎症渗出物中三种不同的脂类代谢产物，并将Cyp1a1/1a2/1b1(-/-)C57BL/6J背景三基因敲除小鼠与C57BL/6J野生型小鼠进行比较。未经处理的三基因敲除小鼠和野生型小鼠在腹膜细胞数量、类型或涉及11个已确定的代谢步骤的基础CYP1活性方面没有发现显著差异。在酵母多糖引发的炎症之后，鉴定出18种脂类介体，包括二十烷基类成员和专门化的亲解介体，即分解素和保护素。与野生型小鼠相比，Cyp1三基因敲除小鼠在酵母多糖处理的腹膜渗出液中表现出更多的中性粒细胞募集。酵母多糖刺激与8个代谢步骤显著相关：花生四烯酸源性白三烯B4(LTB4)增加，5S-羟基二十碳四烯酸(5S-HETE)减少；二十二碳六烯酸衍生神经保护蛋白D1/保护素D1(NPD1/PD1)、17S-羟基二十二碳六烯酸(17S-HDHA)和14S-HDHA减少；二十碳五烯酸衍生的18R-羟基二十碳五烯酸(18R-HEPE)、15S-HEPE和12S-HEPE减少。在体外分析的中性粒细胞中，LTB4水平的升高与中性粒细胞数量的增加是平行的，在Cyp1三基因敲除小鼠中发现20-羟基-LTB4的形成是缺乏的。综上所述，这些结果表明，CYP1酶对调节中性粒细胞炎症的脂质介质的局部代谢物谱有新的贡献。
Currently, all three cytochrome P450 1 (CYP1) monooxygenases are believed to participate in lipid mediator biosynthesis and/or their local inactivation; however, distinct metabolic steps are current unknown. We used multiple-reaction monitoring and LC-UV-MS/MS-based lipid-mediator metabololipidomics to identify and quantify three different lipid-mediator metabolomes in basal peritoneal and zymosan-stimulated inflammatory exudates, comparing Cyp1a1/1a2/1b1(–/–) C57BL/6J-background triple-knockout with C57BL/6J wild-type mice. Significant differences between untreated triple-knockout and wild-type mice were not found for peritoneal cell number or type, or basal CYP1 activities involving 11 identified metabolic steps. Following zymosan-initiated inflammation, 18 lipid mediators were identified including members of the eicosanoids and specialized pro-resolving mediators, i.e. resolvins and protectins. Compared with wild-type mice, Cyp1 triple-knockout mice exhibited increased neutrophil recruitment in zymosan-treated peritoneal exudates. Zymosan stimulation was associated with 8 statistically significantly altered metabolic steps: increased arachidonic acid-derived leukotriene B4 (LTB4) and decreased 5S-hydroxyeicosatetraenoic acid (5S-HETE); decreased docosahexaenoic acid-derived neuroprotectin D1/protectin D1 (NPD1/PD1), 17S-hydroxydocosahexaenoic acid (17S-HDHA), and 14S-HDHA; and decreased eicosapentaenoic acid-derived 18R-hydroxyeicosapentaenoic acid (18R-HEPE), 15S-HEPE, and 12S-HEPE. In neutrophils analyzed ex vivo, elevated LTB4 levels were shown to parallel increased neutrophil numbers, and 20-hydroxy-LTB4 formation was found to be deficient in Cyp1 triple-knockout mice. Together, these results demonstrate novel contributions of CYP1 enzymes to the local metabolite profile of lipid mediators that regulate neutrophilic inflammation.
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影响因子：
64.8
作者：
Chiang, Nan;Fredman, Gabrielle;Backhed, Fredrik;Oh, Sungwhan F.;Vickery, Thad;Schmidt, Birgitta A.;Serhan, Charles N.
通讯作者：
Serhan, Charles N.
影响因子：
15.9
作者：
Ji RR;Xu ZZ;Strichartz G;Serhan CN
通讯作者：
Serhan CN
DOI：
10.4049/jimmunol.1100150
发表时间：
2011-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Campbell EL;Serhan CN;Colgan SP
通讯作者：
Colgan SP
影响因子：
15.9
作者：
Nakagawa, Kiyoshi;Holla, Vijaykumar R.;Capdevila, Jorge H.
通讯作者：
Capdevila, Jorge H.
影响因子：
3.9
作者：
Cheung, C;Yu, AM;Gonzalez, FJ
通讯作者：
Gonzalez, FJ