Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis
Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis
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DOI：
10.1073/pnas.0601280103
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发表时间：
2006-07-25
影响因子：
11.1
通讯作者：
Kang, Jing X.
中科院分区：
文献类型：
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作者：
Hudert, Christian A.;Weylandt, Karsten H.;Kang, Jing X.
Omega-6(n-6)和omega-3(n-3)多不饱和脂肪酸(PUFA)是强效脂质介质的前体，在炎症调节中发挥重要作用。一般来说，n-6多不饱和脂肪酸促进炎症，而n-3多不饱和脂肪酸具有抗炎特性，传统上归因于它们能够抑制n-6多不饱和脂肪酸衍生的促炎二十烷类化合物的形成。新发现的解毒素和保护素是直接来自n-3多不饱和脂肪酸的有效抗炎-脂介质，具有不同的作用途径。然而，n-3多不饱和脂肪酸组织状态在这些抗炎介质形成中的作用尚未得到解决。在这里，我们显示了转基因小鼠中n-3PUFA组织状态的增加，从n-6PUFA内源性生物合成n-3PUFA导致显著的抗炎分解素的形成，并有效地减少结肠炎的炎症和组织损伤。N-3多不饱和脂肪酸及其相关产物的内源性增加并没有减少n-6多不饱和脂肪酸衍生的脂质介质，如白三烯B4和前列腺素E2。所观察到的炎症保护作用可能是由于降低了NF-kappaB的活性和肿瘤坏死因子α、诱导型一氧化氮合酶和IL-1β的表达，并增强了粘膜保护作用，可能是由于三叶因子3、Toll相互作用蛋白和闭锁带-1的高表达所致。这些结果为研究n-3多不饱和脂肪酸衍生的脂质介质建立了一种新的实验模型。他们深入了解了n-3多不饱和脂肪酸通过形成解除素和保护素而不是抑制n-6多不饱和脂肪酸衍生二十烷类化合物的形成而提供的炎症保护的分子机制。
Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are the precursors of potent lipid mediators and play an important role in regulation of inflammation. Generally, n-6 PUFA promote inflammation whereas n-3 PUFA have anti inflammatory properties, traditionally attributed to their ability to inhibit the formation of n-6 PUFA-derived proinflammatory eicosanoids. Newly discovered resolvins and protectins are potent antiinflammatory-lipid mediators derived directly from n-3 PUFA with distinct pathways of action. However, the role of the n-3 PUFA tissue status in the formation of these antiinflammatory mediators has not been addressed. Here we show that an increased n-3 PUFA tissue status in transgenic mice that endogenously biosynthesize n-3 PUFA from n-6 PUFA leads to significant formation of anti inflammatory resolvins and effective reduction in inflammation and tissue injury in colitis. The endogenous increase in n-3 PUFA and related products did not decrease n-6 PUFA-derived lipid mediators such as leukotriene B4 and prostaglandin E2. The observed inflammation protection might result from decreased NF-kappa B activity and expression of TNF alpha, inducible NO synthase, and IL-1 beta, with enhanced muco-protection probably because of the higher expression of trefoil factor 3, Toll-interacting protein, and zonula occludens-1. These results thus establish the fat-1 transgenic mouse as a new experimental model for the study of n-3 PUFA-derived lipid mediators. They add insight into the molecular mechanisms of inflammation protection afforded by n-3 PUFA through formation of resolvins and protectins other than inhibition of n-6 PUFA-derived eicosanoid formation.