Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Immunology. 2014 Sep;143(1):81-95. doi: 10.1111/imm.12296.
Docosahexaenoic acid (DHA) is one of the major ingredients of fish oil and has been reported to have anti-inflammatory properties mediated through the GPR120 receptor. Whether cytosolic phospholipase A2 (cPLA2 ) and lipid mediators produced from cPLA2 activation are involved in the anti-inflammatory role of DHA in macrophages has not been reported. We report here that DHA and the GPR120 agonist, GW9508, activate cPLA2 and cyclooxygenase 2 (COX-2), and cause prostaglandin E2 (PGE2) release in a murine macrophage cell line RAW264.7 and in human primary monocyte-derived macrophages. DHA and GW9508 activate cPLA2 via GPR120 receptor, G protein Gαq and scaffold protein β-arrestin 2. Extracellular signal-regulated kinase 1/2 activation is involved in DHA- and GW9508-induced cPLA2 activation, but not p38 mitogen-activated protein kinase. The anti-inflammatory role of DHA and GW9508 is in part via activation of cPLA2 , COX-2 and production of PGE2 as a cPLA2 inhibitor or a COX-2 inhibitor partially reverses the DHA- and GW9508-induced inhibition of lipopolysaccharide-induced interleukin-6 secretion. The cPLA2 product arachidonic acid and PGE2 also play an anti-inflammatory role. This effect of PGE2 is partially through inhibition of the nuclear factor-κB signalling pathway and through the EP4 receptor of PGE2 because an EP4 inhibitor or knock-down of EP4 partially reverses DHA inhibition of lipopolysaccharide-induced interleukin-6 secretion. Hence, DHA has an anti-inflammatory effect partially through induction of PGE2.
二十二碳六烯酸 (DHA) 是鱼油的主要成分之一，据报道，它具有通过 GPR120 受体介导的抗炎特性。DHA 是否通过细胞质磷脂酶 A2(cPLA2) 和 cPLA2 激活产生的脂质介质发挥抗炎作用，在巨噬细胞中尚未报道。我们在这里报告，DHA 和 GPR120 激动剂 GW9508 激活 cPLA2 和环氧化酶 2 (COX-2)，并导致前列腺素 E2 (PGE2) 在鼠巨噬细胞系 RAW264.7 和人原代单核细胞衍生的巨噬细胞中释放。DHA 和 GW9508 通过 GPR120 受体、G 蛋白 Gαq 和支架蛋白 β-arrestin 2 激活 cPLA2。细胞外信号调节激酶 1/2 的激活参与 DHA 和 GW9508 诱导的 cPLA2 激活，但不参与 p38 丝裂原激活蛋白激酶。DHA 和 GW9508 的抗炎作用部分是通过激活 cPLA2、COX-2 和产生 PGE2 作为 cPLA2 抑制剂或 COX-2 抑制剂部分逆转 DHA 和 GW9508 诱导的脂多糖诱导的白细胞介素-6 分泌抑制。cPLA2 产物花生四烯酸和 PGE2 也发挥抗炎作用。这种 PGE2 的作用部分是通过抑制核因子-κB 信号通路和通过 PGE2 的 EP4 受体实现的，因为 EP4 抑制剂或 EP4 的敲低部分逆转了 DHA 抑制脂多糖诱导的白细胞介素-6 分泌。因此，DHA 通过诱导 PGE2 发挥抗炎作用。
