Liu Kai-Li, Yang Ya-Chen, Yao Hsien-Tsung, Chia Ting-Wen, Lu Chia-Yang, Li Chien-Chun, Tsai Henry J, Lii Chong-Kuei, Chen Haw-Wen
School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan.
Mol Nutr Food Res. 2016 Feb;60(2):430-43. doi: 10.1002/mnfr.201500178. Epub 2015 Dec 9.
Inflammation is intimately associated with many cardiovascular events and docosahexaenoic acid (DHA) has been shown to protect against CVD. Egr-1 has emerged as a key regulator in the development of atherosclerosis. Free fatty acid receptor 4 (FFA4) is an n-3 FA membrane receptor. Tumor necrosis factor alpha (TNF-α) is an inflammatory mediator and transforming growth factor-β-activated kinase 1 (TAK1) is essential in the TNF-α-mediated activation of NF-κB. We examined the mechanisms underlying DHA inhibition of inflammation in human EA.hy926 cells.
TNF-α markedly induced the interaction between TAK1 binding protein (TAB) 2 and TAK1/TAB1, the phosphorylation of ERK, p38 MAPK and Akt, the expression of Egr-1 and ICAM-1, and HL-60 (monocyte-like) cell adhesion. Pretreatment with DHA attenuated TNF-α-induced phosphorylation of ERK, expression of Egr-1 and ICAM-1 and HL-60 cell adhesion. Transfection with siFFA4 reversed the DHA-mediated inhibition of TNF-α-induced Egr-1 and ICAM-1 expression, HL-60 cell adhesion and NF-κB and DNA-binding activity.
Our results suggest that the anti-inflammatory effect of DHA on the endothelium is at least partially linked to FFA4, disruption of TAB2 interaction with TAK1/TAB1 and downregulation of ERK-dependent Egr-1 and ICAM-1 expression, which leads to less HL-60 cell adhesion to TNF-α-stimulated EA.hy926 cells.
炎症与许多心血管事件密切相关，二十二碳六烯酸（DHA）已被证明可预防心血管疾病（CVD）。Egr-1已成为动脉粥样硬化发展中的关键调节因子。游离脂肪酸受体4（FFA4）是一种n-3脂肪酸膜受体。肿瘤坏死因子α（TNF-α）是一种炎症介质，转化生长因子-β激活激酶1（TAK1）在TNF-α介导的NF-κB激活中至关重要。我们研究了DHA抑制人EA.hy926细胞炎症的潜在机制。
TNF-α显著诱导TAK1结合蛋白（TAB）2与TAK1/TAB1之间的相互作用、ERK、p38丝裂原活化蛋白激酶（MAPK）和Akt的磷酸化、Egr-1和细胞间黏附分子-1（ICAM-1）的表达以及HL-60（单核细胞样）细胞黏附。DHA预处理减弱了TNF-α诱导的ERK磷酸化、Egr-1和ICAM-1的表达以及HL-60细胞黏附。用小干扰RNA（siRNA）FFA4转染可逆转DHA介导的对TNF-α诱导的Egr-1和ICAM-1表达、HL-60细胞黏附以及NF-κB与DNA结合活性的抑制作用。
我们的结果表明，DHA对内皮细胞的抗炎作用至少部分与FFA4、TAB2与TAK1/TAB1相互作用的破坏以及ERK依赖性Egr-1和ICAM-1表达的下调有关，这导致HL-60细胞与TNF-α刺激的EA.hy926细胞的黏附减少。
