A Novel Long Chain Polyunsaturated Fatty Acid, β-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), 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 (IC50 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 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.

The Immunomodulatory Effects of Novel β-Oxa, β-Thia, and γ-Thia Polyunsaturated Fatty Acids on Human T Lymphocyte Proliferation, Cytokine Production, and Activation of Protein Kinase C and MAPKs

“…␤-oxa, ␤-thia, and ␥-thia PUFA and their methyl esters were synthesized, as described previously (5)(6)(7)(8). All fatty acid stocks (20 mM in chloroform or ethanol) were stored at Ϫ20°C.…”

“…Recently, we have demonstrated that one of these, ␤-oxa 21: 3n-3, had similar biological properties as the 15-hydroperoxyeicosatetraenoic acid (15-HPETE), which markedly depressed T cell function and the inflammatory response, but was a poor stimulator of the respiratory burst in neutrophils (7). The availability of a range of novel PUFA with different structural modifications has enabled us to better define the relationship between specific structural elements of these novel fats and their biological properties.…”

Aspirin-Triggered Lipoxin A4 and B4 Analogs Block Extracellular Signal-Regulated Kinase-Dependent TNF-α Secretion from Human T Cells

“…pecific lipid-derived mediators can exert opposing actions on T cell proinflammatory functions (1)(2)(3). The key role of the classic eicosanoids, such as the prostanoids in the regulation of inflammatory and autoimmune disorders, is also well appreciated (4).…”

“…The key role of the classic eicosanoids, such as the prostanoids in the regulation of inflammatory and autoimmune disorders, is also well appreciated (4). In rheumatoid arthritis, which is mediated in part by the activation and recruitment of Ag-specific lymphocytes (5), leukotriene (LT) 3 B 4 generated locally can control T cell activation, regulating the inflammatory response (6,7).…”

The Effect of the JNK Inhibitor, JIP Peptide, on Human T Lymphocyte Proliferation and Cytokine Production

“…29). T cells were then stimulated for 48 h with PHA (2 g/ml; Murex Diagnostics and PMA (10 ng/ml; Sigma-Aldrich)) diluted in RPMI 1640 containing 5% heat-inactivated blood group AB serum (5% ⌬AB serum) at 37°C in 5% CO 2 and high humidity.…”