Cytochrome P-450 4F18 Is the Leukotriene B4 ω-1/ω-2 Hydroxylase in Mouse Polymorphonuclear Leukocytes
Year: 2005
Type: article
Abstract: Leukotriene B(4) (LTB(4)) is a potent chemoattractant for polymorphonuclear leukocytes (PMN) and other cells. Human PMN inactivate LTB(4) by omega-oxidation catalyzed by cytochrome P-450 (CYP) 4F3A. The contribution of the enzymatic inactivation of LTB(4) by CYP4Fs to down-regulating functional responses of cells to LTB(4) is unknown. To elucidate the role of CYP4F-mediated inactivation of LTB(4) in terminating the responses of PMN to LTB(4) 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 LTB(4) in mouse myeloid cells as CYP4F18. As determined by mass spectrometry, this enzyme catalyzes the conversion of LTB(4) to 19-OH LTB(4) and to a lesser extent 18-OH LTB(4). Inhibition of CYP4F18 resulted in a marked increase in calcium flux and a 220% increase in the chemotactic response of mouse PMN to LTB(4). CYP4F18 expression was induced in bone marrow-derived dendritic cells by bacterial lipopolysaccharide, a ligand for TLR4, and by poly(I.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 LTB(4) metabolism and functional responses in mouse PMN and identify it as the functional orthologue of human PMN CYP4F3A.
Source: Journal of Biological Chemistry
Authors: Peter Christmas, Karine Tolentino, Valeria Primo, Karin Zemski Berry, Robert C. Murphy, Mei Chen, David M. Lee, Roy J. Soberman
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: PHARMACOLOGY OF 4F CYTOCHROME P450'S, G3224647842, Synovial mast cells in inflammatory arthritis, SYNOVIAL CADHERIN 11 AND ITS COUNTER-RECEPTOR, Physiologic Regulation of Hematopoiesis by Notch, Tcell tolerization in the treatment of Type I diabetes, G5722973536, The role of the CYP4F3 gene in inflammation, G6735912124, G6789690239, Leukotrienes and Slow Reacting Substance of Anaphylaxis, G9000055564
OpenAlex ID: W2081429238