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Contributions of the three CYP1 monooxygenases to pro-inflammatory and inflammation-resolution lipid mediator pathways.
Divanovic, Senad; Dalli, Jesmond; Jorge-Nebert, Lucia F; Flick, Leah M; Gálvez-Peralta, Marina; Boespflug, Nicholas D; Stankiewicz, Traci E; Fitzgerald, Jonathan M; Somarathna, Maheshika; Karp, Christopher L; Serhan, Charles N; Nebert, Daniel W.
Afiliación
  • Divanovic S; Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati OH 45229.
  • Dalli J; Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
  • Jorge-Nebert LF; Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056.
  • Flick LM; Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati OH 45229.
  • Gálvez-Peralta M; Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056.
  • Boespflug ND; Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati OH 45229.
  • Stankiewicz TE; Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati OH 45229.
  • Fitzgerald JM; Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
  • Somarathna M; Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056.
  • Karp CL; Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati OH 45229.
  • Serhan CN; Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
  • Nebert DW; Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056.
J Immunol ; 191(6): 3347-57, 2013 Sep 15.
Article en En | MEDLINE | ID: mdl-23956430
ABSTRACT
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 unknown. We used multiple-reaction monitoring and liquid chromatography-UV coupled with tandem mass spectrometry-based lipid-mediator metabololipidomics to identify and quantify three lipid-mediator metabolomes in basal peritoneal and zymosan-stimulated inflammatory exudates, comparing Cyp1a1/1a2/1b1(⁻/⁻) C57BL/6J-background triple-knockout mice 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 for basal CYP1 activities involving 11 identified metabolic steps. Following zymosan-initiated inflammation, 18 lipid mediators were identified, including members of the eicosanoids and specialized proresolving 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 eight statistically significantly altered metabolic

steps:

increased arachidonic acid-derived leukotriene B4 (LTB4) and decreased 5S-hydroxyeicosatetraenoic acid; decreased docosahexaenoic acid-derived neuroprotectin D1/protectin D1, 17S-hydroxydocosahexaenoic acid, and 14S-hydroxydocosahexaenoic acid; and decreased eicosapentaenoic acid-derived 18R-hydroxyeicosapentaenoic acid (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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Transducción de Señal / Mediadores de Inflamación / Sistema Enzimático del Citocromo P-450 / Inflamación Límite: Animals / Humans Idioma: En Revista: J Immunol Año: 2013 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Transducción de Señal / Mediadores de Inflamación / Sistema Enzimático del Citocromo P-450 / Inflamación Límite: Animals / Humans Idioma: En Revista: J Immunol Año: 2013 Tipo del documento: Article