Cyclooxygenase-2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4)
Cyclooxygenase-2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4)
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DOI：
10.1096/fj.13-235333
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发表时间：
2013-12-01
期刊：
影响因子：
4.8
通讯作者：
Funk, Colin D.
中科院分区：
文献类型：
--
作者：
Li, Xinzhi;Yu, Ying;Funk, Colin D.
环氧合酶 2 (COX-2) 衍生的前列腺素与多种炎症性疾病有关。这些研究的目的是通过脂多糖 (LPS) 攻击的小鼠 RAW 264.7 细胞和腹膜巨噬细胞中的游离脂肪酸受体 4 (FFA4) 信号通路，检查以前未探索过的 COX-2 诱导和二十二碳六烯酸 (DHA) 之间的相互作用。 DHA 剂量（IC50 = 18 μM）和时间依赖性地降低 COX-2 表达，而不影响 COX-1。 DHA（25 μM，持续 24 小时）可将 LPS 诱导的前列腺素 E-2 (PGE(2)) 合成降低 81%，主要是通过减少 COX-2 (60%) 以及下调微粒体前列腺素 E 合酶-1 (46%)，但与过氧化物酶体增殖物激活受体无关。 FFA4 敲低消除了 DHA 对 COX-2 诱导、PGE2 产生和白细胞介素 6 (IL-6) 基因表达的影响。在存在通过 COX-2、12/15-脂氧合酶和 CYP450 进行类二十烷酸代谢的抑制剂（罗非昔布 (1 μM)、PD146176 (2 μM) 或 MS-PPOH (20 μM)）时，DHA 仍能有效减弱 COX-2 诱导。此外，通过 Akt/JNK 磷酸化和 p65 核转位的 Toll 样受体 4 信号传导被 DHA 激活的 FFA4 与 β-arrestin 2 偶联所抑制，而 FFA4 敲低则可逆转这一现象。这些数据支持DHA部分通过FFA4调节COX-2表达和活性，这为DHA的一些抗炎作用提供了新的机制解释。
Cyclooxygenase-2 (COX-2)-derived prostaglandins are implicated in numerous inflammatory disorders. The purpose of these studies was to examine previously unexplored interactions between COX-2 induction and docosahexaenoic acid (DHA) via the free fatty acid receptor 4 (FFA4) signaling pathway in murine RAW 264.7 cells and peritoneal macrophages challenged with lipopolysaccharide (LPS). DHA dose (IC50 = 18 mu M)- and time-dependently reduced COX-2 expression, without affecting COX-1. DHA (25 mu M for 24 h) decreased LPS-induced prostaglandin E-2 (PGE(2)) synthesis by 81%, primarily through reducing COX-2 (60%), as well as down-regulating microsomal prostaglandin E synthase-1 (46%), but independently of peroxisome proliferator-activated receptors. FFA4 knockdown abrogated DHA effects on COX-2 induction, PGE2 production, and interleukin 6 (IL-6) gene expression. In the presence of inhibitors of eicosanoid metabolism via COX-2, 12/15-lipoxygenase and CYP450s (rofecoxib (1 mu M), PD146176 (2 mu M), or MS-PPOH (20 mu M)), DHA was still effective in attenuating COX-2 induction. Moreover, Toll-like receptor 4 signaling via Akt/JNK phosphorylation and p65 nuclear translocation was repressed by DHA-activated FFA4 coupling with beta-arrestin 2, which was reversed by FFA4 knockdown. These data support DHA modulation of COX-2 expression and activity, in part, via FFA4, which provides a new mechanistic explanation for some of the anti-inflammatory effects of DHA.