title: A novel beta-oxa polyunsaturated fatty acid downregulates the activation of the IkappaB kinase/nuclear factor kappaB pathway, inhibits expression of endothelial cell adhesion molecules, and depresses inflammation.
abstract: Several novel polyunsaturated fatty acids (PUFAs) that contain either an oxygen or sulfur atom in the beta-position were found to exhibit more selective antiinflammatory properties than their natural PUFA counterparts. One of these, beta-oxa-23:4n-6, unlike natural PUFAs, lacked ability to stimulate oxygen radical production in neutrophils but caused marked inhibition of agonist-induced upregulation of leukocyte adhesion to cultured human umbilical vein endothelial cells (HUVEC) and E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 expression. In addition, beta-oxa-23:4n-6 inhibited acute and chronic inflammatory responses in mice as well as the upregulation of adhesion molecule expression in arterial endothelium. This action of beta-oxa-23:4n-6 required a functional 12- but not 5-lipoxygenase or cyclooxygenases, consistent with its metabolism via the 12-lipoxygenase pathway. Whereas beta-oxa-23:4n-6 did not affect the activation of mitogen-activated protein kinases by tumor necrosis factor, activation of the IkappaB kinase/nuclear factor kappaB pathway was selectively inhibited. These novel PUFAs could form the basis for a potential new class of pharmaceuticals for treating inflammatory diseases, including atherosclerosis.
authors.affiliation: Department of Immunopathology, Women's and Children's Hospital, University of Adelaide, South Australia, Australia. antonio.ferrante@adelaide.edu.au
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrante
authors.forename: Brenton S
authors.initials: BS
authors.lastname: Robinson
authors.forename: Harmeet
authors.initials: H
authors.lastname: Singh
authors.forename: Hubertus P A
authors.initials: HP
authors.lastname: Jersmann
authors.forename: Judith V
authors.initials: JV
authors.lastname: Ferrante
authors.forename: Zhi H
authors.initials: ZH
authors.lastname: Huang
authors.forename: Neil A
authors.initials: NA
authors.lastname: Trout
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pitt
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Rathjen
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Easton
authors.forename: Alf
authors.initials: A
authors.lastname: Poulos
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Prager
authors.forename: Frank S
authors.initials: FS
authors.lastname: Lee
authors.forename: Charles S T
authors.initials: CS
authors.lastname: Hii
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D001092:Arachidonate 12-Lipoxygenase / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000502:physiology; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology; D016897:Respiratory Burst / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D005231:Fatty Acids, Unsaturated; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D001092:Arachidonate 12-Lipoxygenase; D051550:I-kappa B Kinase