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Inflammation resolved by retinoid X receptor-mediated inactivation of leukotriene signaling pathways

Auinash Kalsotra^*, Liping Du, Ying Wang^*, Patricia A. Ladd, Yasushi Kikuta, Madeleine Duvic^||, Alan S. Boyd, Diane S. Keeney^, and Henry W. Strobel^*,1

^* Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, Texas, USA; Departments of

Biochemistry and

Medicine/Dermatology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA;

Department of Applied Biological Science, Fukuyama University, Fukuyama, Hiroshima, Japan; and

^|| Department of Dermatology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

¹ Correspondence: University of Texas Health Science Center at Houston, 6431 Fannin St., Medical School Bldg. 6, Room 200, Houston, TX 77030, USA. E-mail: henry.w.strobel{at}uth.tmc.edu

Leukotrienes are implicated in the pathogenesis of diverse, inflammation-driven diseases. Metabolic inactivation of leukotriene signaling is an innate response to resolve inflammation, yet little is known of mechanisms regulating disposition of leukotrienes in peripheral tissues afflicted in common inflammatory diseases. We studied leukotriene hydroxylases (CYP4F gene products) in human skin, a common target of inflammation and adverse drug reactions. Epidermal keratinocytes express at least six CYP4F enzymes; the most highly expressed and highly regulated is CYP4F3A—the main neutrophil leukotriene hydroxylase. Differentiation-specific factors and retinoids are positive CYP4F regulators in vitro, effecting increased leukotriene B4 hydroxylation (inactivation). CYP4F expression is up-regulated in situ in hyperproliferative dermatoses—an innate mechanism to repair and restore epidermal barrier competency—and after retinoid therapy. Enhanced CYP4F-mediated inactivation of leukotriene signaling is a previously unrecognized antiinflammatory property of therapeutic retinoids mediated by preferential interactions between retinoid X receptors and CYP4F promoter elements in epidermal cells.—Kalsotra, A., Du, L., Wang, Y., Ladd, P. A., Kikuta, Y., Duvic, M., Boyd, A. S., Keeney, D. S., Strobel, H. W. Inflammation resolved by retinoid X receptor-mediated inactivation of leukotriene signaling pathways.

Key Words: cytochromes P450 4F • epidermal inflammation • resolution signals