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
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
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DOI：
10.4049/jimmunol.174.1.233
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发表时间：
2005-01-01
影响因子：
4.4
通讯作者：
Ferrante, A
中科院分区：
文献类型：
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作者：
Costabile, M;Hii, CST;Ferrante, A
我们最近已经证明，一种新的n-3长链多不饱和脂肪酸（PUFA）（β-氧杂21：3 n-3）是一种比n-3 PUFA更有效和更有选择性的抗炎剂。为了进一步了解这项技术，我们合成了其他由β-氧杂、β-硫杂和γ-硫杂化合物组成的新型PUFA。所有三种类型都显示出抗炎活性。每种不饱和β-氧杂脂肪酸显示出对PHA-PMA诱导的T细胞增殖的类似抑制，同时对TNF-β产生具有平行抑制。而beta-oxa 25：6 n-3和beta-oxa 21：4 n-3对IFN-γ产生的抑制作用较弱。令人惊讶的是，β-oxa 23：4 n-6和β-oxa 21：3 n-6对IL-2产生具有边际效应。因此，结构变异可以产生对不同免疫学参数的选择性。β-硫杂化合物23：4 n-6、21：3 n-6和21：3 n-3在抑制所有免疫应答方面高度有效。在所测试的两种γ-硫杂PUFA中，γ-硫杂24：4 n-6是除IL-2之外的所有反应的强抑制剂，但γ-硫杂22：3 n-6具有非常小的抑制作用。对两种最具活性的化合物β-硫杂23：4 n-6和β-硫杂21：3 n-6进行了更详细的研究，并显示在最佳条件下具有1-2 μ M的IC 50。因此，这些PUFA保留了n-3 PUFA，20：5 n-3和22：6 n-3的免疫抑制特性，但没有嗜中性粒细胞刺激特性。它们对T淋巴细胞的作用不依赖于环氧合酶或脂氧合酶的活性，它们通过抑制蛋白激酶C和ERK 1/ERK 2激酶的活化而在受体结合后水平起作用。
We have recently demonstrated that a novel n-3 long chain polyunsaturated fatty acid (PUFA) (beta-oxa 21:3n-3) was a more potent and more selective anti-inflammatory agent than n-3 PUFA. To gain further insights into this technology, we synthesized other novel PUFA consisting of beta-oxa, beta-thia, and gamma-thia compounds. All three types displayed anti-inflammatory activity. Each of the unsaturated beta-oxa fatty acids showed similar inhibition of PHA-PMA-induced T cell proliferation with a parallel inhibition of TNF-beta production. However, beta-oxa 25:6n-3 and beta-oxa 21:4n-3 displayed lower inhibitory action on IFN-gamma production. Surprisingly, beta-oxa 23:4n-6 and beta-oxa 21:3n-6 had marginal effect on IL-2 production. Thus, structural variation can generate selectivity for different immunological parameters. The beta-thia compounds 23:4n-6, 21:3n-6, and 21:3n-3 were highly effective in inhibiting all immunological responses. Of the two gamma-thia PUFA tested, gamma-thia 24:4n-6 was a strong inhibitor of all responses apart from IL-2, but gamma-thia 22:3n-6 had very little inhibitory effect. Two of the most active compounds, beta-thia 23:4n-6 and beta-thia 21:3n-6, were studied in more detail and shown to have an IC50 of 1-2 muM under optimal conditions. Thus, these PUFA retain the immunosuppressive properties of the n-3 PUFAs, 20:5n-3 and 22:6n-3, but not the neutrophil-stimulating properties. Their action on T lymphocytes is independent of cyclooxygenase or lipoxygenase activity, and they act at a postreceptor-binding level by inhibiting the activation of protein kinase C and ERK1/ERK2 kinases.