title: A novel long chain polyunsaturated fatty acid, beta-Oxa 21:3n-3, inhibits T lymphocyte proliferation, cytokine production, delayed-type hypersensitivity, and carrageenan-induced paw reaction and selectively targets intracellular signals.
abstract: A novel polyunsaturated fatty acid (PUFA), beta-oxa 21:3n-3, containing an oxygen atom in the beta position, was chemically synthesized, and found to have more selective biological activity than the n-3 PUFA, docosahexaenoic acid (22:6n-3) on cells of the immune system. Although beta-oxa 21:3n-3 was very poor compared with 22:6n-3 at stimulating oxygen radical production in neutrophils, it was more effective at inhibiting human T lymphocyte proliferation (IC(50) of 1.9 vs 5.2 microM, respectively). beta-Oxa 21:3n-3 also inhibited the production of TNF-beta, IFN-gamma, and IL-2 by purified human T lymphocytes stimulated with PHA plus PMA, anti-CD3 plus anti-CD28 mAbs, or PMA plus A23187. Metabolism of beta-oxa 21:3n-3 via the cyclooxygenase and lipoxygenase pathways was not required for its inhibitory effects. Consistent with its ability to suppress T lymphocyte function, beta-oxa 21:3n-3 significantly inhibited the delayed-type hypersensitivity response and carrageenan-induced paw edema in mice. In T lymphocytes, beta-oxa 21:3n-3 inhibited the agonist-stimulated translocation of protein kinase C-betaI and -epsilon, but not -alpha, -betaII, or -theta to a particulate fraction, and also inhibited the activation of the extracellular signal-regulated protein kinase, but not c-Jun NH(2)-terminal kinase and p38. In contrast, 22:6n-3 had no effects on these protein kinase C isozymes. The increase in antiinflammatory activity and loss of unwanted bioaction through the generation of a novel synthetic 22:6n-3 analogue provides evidence for a novel strategy in the development of anti-inflammatory agents by chemically engineering PUFA.
authors.affiliation: Department of Immunopathology and Paediatrics, University of Adelaide, Women's and Children's Hospital, 72 King William Road, North Adelaide, 5006 South Australia.
authors.forename: M
authors.initials: M
authors.lastname: Costabile
authors.forename: C S
authors.initials: CS
authors.lastname: Hii
authors.forename: B S
authors.initials: BS
authors.lastname: Robinson
authors.forename: D A
authors.initials: DA
authors.lastname: Rathjen
authors.forename: M
authors.initials: M
authors.lastname: Pitt
authors.forename: C
authors.initials: C
authors.lastname: Easton
authors.forename: R C
authors.initials: RC
authors.lastname: Miller
authors.forename: A
authors.initials: A
authors.lastname: Poulos
authors.forename: A W
authors.initials: AW
authors.lastname: Murray
authors.forename: A
authors.initials: A
authors.lastname: Ferrante
mesh_terms: D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D002351:Carrageenan; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D003593:Cytoplasm / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy*; D008213:Lymphocyte Activation / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000276:immunology; D011493:Protein Kinase C / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; C439390:beta-Oxa 21-3n-3 fatty acid; D004281:Docosahexaenoic Acids; D002351:Carrageenan; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases