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J. Biol. Chem., Vol. 281, Issue 11, 7189-7196, March 17, 2006

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Cytochrome P-450 4F18 Is the Leukotriene B₄ -1/-2 Hydroxylase in Mouse Polymorphonuclear Leukocytes

IDENTIFICATION AS THE FUNCTIONAL ORTHOLOGUE OF HUMAN POLYMORPHONUCLEAR LEUKOCYTE CYP4F3A IN THE DOWN-REGULATION OF RESPONSES TO LTB₄^*

Peter Christmas, Karine Tolentino, Valeria Primo, Karin Zemski Berry, Robert C. Murphy, Mei Chen^¶, David M. Lee^¶, and Roy J. Soberman¹

From the Renal Unit and Department of Medicine, Massachusetts General Hospital (East), Charlestown, Massachusetts 02129, the Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, Colorado 80045, and the ^¶Division of Rheumatology and Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts 02115

Leukotriene B₄ (LTB₄) is a potent chemoattractant for polymorphonuclear leukocytes (PMN) and other cells. Human PMN inactivate LTB₄ by -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 -1 and -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·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.

Received for publication, December 8, 2005

^* This work was supported by National Institutes of Health Grants GM-61823 (to R. J. S.), DK59991 (to P. C.), 5R01HL025785-25 (to R. C. M.), 5R01HL068256-03 (to N. C.), R01HL25785 (to R. C. M.), K08 AR 02214-04 and R01 AI 059746-02 (to D. L.), R03DK067940 and the Patricia Weilder Young Investigator Award from the National Kidney Foundation (to B. N.), and a gift from the Jewish Communal Fund (to R. J. S). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Renal Unit and Dept. of Medicine, MA General Hospital (East), Bldg 149, Navy Yard, 13th St., Charlestown, MA 02129. Tel.: 617-726-3747; Fax: 617-726-5669; E-mail: soberman{at}helix.mgh.harvard.edu.

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