A novel long chain polyunsaturated fatty acid, β-Oxa 21: 3n-3, inhibits T lymphocyte proliferation, cytokine production, delayed-type hypersensitivity, and carrageenan …

M Costabile, CST Hii, BS Robinson… - The Journal of …, 2001 - journals.aai.org
M Costabile, CST Hii, BS Robinson, DA Rathjen, M Pitt, C Easton, RC Miller, A Poulos…
The Journal of Immunology, 2001journals.aai.org
A novel polyunsaturated fatty acid (PUFA), β-oxa 21: 3n-3, containing an oxygen atom in the
β 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 β-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 μM, respectively). β-Oxa 21: 3n-3 also inhibited the …
Abstract
A novel polyunsaturated fatty acid (PUFA), β-oxa 21: 3n-3, containing an oxygen atom in the β 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 β-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 μM, respectively). β-Oxa 21: 3n-3 also inhibited the production of TNF-β, IFN-γ, 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 β-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, β-oxa 21: 3n-3 significantly inhibited the delayed-type hypersensitivity response and carrageenan-induced paw edema in mice. In T lymphocytes, β-oxa 21: 3n-3 inhibited the agonist-stimulated translocation of protein kinase C-βI and-ε, but not-α,-βII, or-θ 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.
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