title: Cytochrome P4504f, a potential therapeutic target limiting neuroinflammation.
abstract: Inflammatory processes are involved in the pathogenesis and/or progression of acute central nervous system (CNS) infection, traumatic brain injury and neurodegenerative disorders among others indicating the need for novel strategies to limit neuroinflammation. Eicosanoids including leukotrienes, particularly leukotriene B(4) (LTB(4)) are principle mediator(s) of inflammatory response, initiating and amplifying the generation of cytokines and chemokines. Cytochrome P450 (Cyp), a family of heme proteins mediate metabolism of xenobiotics and endogenous compounds, such as eicosanoids and leukotrienes. Cytochrome P4504F (Cyp4f) subfamily includes five functional enzymes in mouse. We cloned and expressed the mouse Cyp4f enzymes, assayed their relative expression in brain and examined their ability to hydroxylate the inflammatory cascade prompt LTB(4) to its inactive 20-hydroxylated product. We then examined the role of Cyp4fs in regulating inflammatory response in vitro, in microglial cells and in vivo, in mouse brain using lipopolysacharide (LPS), as a model compound to generate inflammatory response. We demonstrate that mouse brain Cyp4fs are expressed ubiquitously in several cell types in the brain, including neurons and microglia, and modulate inflammatory response triggered by LPS, in vivo and in microglial cells, in vitro through metabolism of LTB(4) to the inactive 20-hydroxy LTB(4). Chemical inhibitor or shRNA to Cyp4fs enhance and inducer of Cyp4fs attenuates inflammatory response. Further, induction of Cyp4f expression lowers LTB(4) levels and affords neuroprotection in microglial cells or mice exposed to LPS. Thus, catalytic activity of Cyp4fs is a novel target for modulating neuroinflammation through hydroxylation of LTB(4).
authors.affiliation: Division of Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Haryana, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Sehgal
authors.forename: Varsha
authors.initials: V
authors.lastname: Agarwal
authors.forename: Rupanagudi Khader
authors.initials: RK
authors.lastname: Valli
authors.forename: Shanker Dutt
authors.initials: SD
authors.lastname: Joshi
authors.forename: Leposava
authors.initials: L
authors.lastname: Antonovic
authors.forename: Henry W
authors.initials: HW
authors.lastname: Strobel
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Ravindranath
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D053308:Lymphotoxin-beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009443:Neuritis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C505887:Ltb protein, mouse; D053308:Lymphotoxin-beta; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C465342:Cyp4f14 protein, mouse