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A Novel Long Chain Polyunsaturated Fatty Acid, -Oxa 21:3n-3, Inhibits T Lymphocyte Proliferation, Cytokine Production, Delayed-Type Hypersensitivity, and Carrageenan-Induced Paw Reaction and Selectively Targets Intracellular Signals¹

Maurizio Costabile^*,, Charles S. T. Hii^*, Brenton S. Robinson^*, Deborah A. Rathjen^2,*, Michael Pitt^3,, Christopher Easton, Robert C. Miller^4,¶, Alf Poulos^5,*, Andrew W. Murray and Antonio Ferrante^6,*,

^* Departments of Immunopathology and Paediatrics, University of Adelaide, Women’s and Children’s Hospital, North Adelaide, South Australia; School of Pharmaceutical, Molecular, and Biomedical Sciences, University of South Australia, South Australia; Research School of Chemistry, Australian National University, Canberra, Australia; School of Biological Sciences, Flinders University, Adelaide, Australia; and ^¶ Peptech Ltd., North Ryde, New South Wales, Australia

A novel polyunsaturated fatty acid (PUFA), -oxa 21:3n-3, containing an oxygen atom in the 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 -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 (IC₅₀ of 1.9 vs 5.2 µM, respectively). -Oxa 21:3n-3 also inhibited the production of TNF-, IFN-, 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 -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, -oxa 21:3n-3 significantly inhibited the delayed-type hypersensitivity response and carrageenan-induced paw edema in mice. In T lymphocytes, -oxa 21:3n-3 inhibited the agonist-stimulated translocation of protein kinase C-I and -, but not -, -II, or - to a particulate fraction, and also inhibited the activation of the extracellular signal-regulated protein kinase, but not c-Jun NH₂-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.

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