Immunomodulation Group, School of Biotechnology, Dublin City University, Dublin 9, Ireland.
J Nutr Biochem. 2013 May;24(5):920-8. doi: 10.1016/j.jnutbio.2012.06.010. Epub 2012 Aug 15.
Polyunsaturated fatty acids (PUFA) can modulate the immune response, however the mechanism by which they exert this effect remains unclear. Previous studies have clearly demonstrated that the cis-9, trans-11 isomer of conjugated linoleic acid (c9,t11-CLA), found predominantly in beef and dairy products, can modulate the response of immune cells to the toll-like receptor (TLR) 4 ligand, lipopolysaccharide (LPS). This study aimed to investigate further the mechanism by which these effects are mediated. Treatment of macrophages with c9,t11-CLA significantly decreased CD14 expression and partially blocked its association with lipid rafts following stimulation with LPS. Furthermore the c9,t11-CLA isomer inhibited both nuclear factor-κB (NF-κB) and IRF3 activation following TLR4 ligation while eicosapentaenoic acid (EPA) only suppressed NF-κB activation. Given that the ability of LPS to activate IRF3 downstream of TLR4 depends on internalisation of the TLR4 complex and involves CD14, we examined TLR4 endocytosis. Indeed the internalisation of TLR4 to early endosomes following activation with LPS was markedly inhibited in c9,t11-CLA treated cells. These effects were not seen with the n-3 fatty acid, EPA, which was used as a comparison. Our data demonstrates that c9,t11-CLA inhibits IRF3 activation via its effects on CD14 expression and localisation. This results in a decrease in the endocytosis of TLR4 which is necessary for IRF3 activation, revealing a novel mechanism by which this PUFA exerts its anti-inflammatory effects.
多不饱和脂肪酸（PUFA）可以调节免疫反应，但其发挥作用的机制尚不清楚。先前的研究清楚地表明，共轭亚油酸（CLA）的顺式-9，反式-11 异构体（c9，t11-CLA）主要存在于牛肉和乳制品中，可以调节免疫细胞对 Toll 样受体（TLR）4 配体脂多糖（LPS）的反应。本研究旨在进一步研究介导这些作用的机制。用 c9，t11-CLA 处理巨噬细胞可显著降低 LPS 刺激后 CD14 的表达，并部分阻断其与脂筏的结合。此外，c9，t11-CLA 异构体抑制 TLR4 连接后核因子-κB（NF-κB）和 IRF3 的激活，而二十碳五烯酸（EPA）仅抑制 NF-κB 的激活。鉴于 LPS 激活 TLR4 下游的 IRF3 取决于 TLR4 复合物的内化，并且涉及 CD14，我们检查了 TLR4 的内化。事实上，用 LPS 激活后，c9，t11-CLA 处理的细胞中 TLR4 向早期内体的内化明显受到抑制。用 n-3 脂肪酸 EPA 进行比较时，没有观察到这种情况。我们的数据表明，c9，t11-CLA 通过其对 CD14 表达和定位的影响来抑制 IRF3 的激活。这导致 TLR4 的内化减少，这对于 IRF3 的激活是必需的，揭示了这种 PUFA 发挥其抗炎作用的新机制。
