Bagga Dilprit, Wang Ling, Farias-Eisner Robin, Glaspy John A, Reddy Srinivasa T
Division of Hematology-Oncology, Department of Obstetrics and Gynecology, University of California, Los Angeles, CA 90095-1679, USA.
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1751-6. doi: 10.1073/pnas.0334211100. Epub 2003 Feb 10.
Omega-6 (omega-6) polyunsaturated fatty acids (PUFA), abundant in the Western diet, are precursors for a number of key mediators of inflammation including the 2-series of prostaglandins (PG). PGE(2), a cyclooxygenase (COX) metabolite of arachidonic acid, a omega-6 PUFA, is a potent mediator of inflammation and cell proliferation. Dietary supplements rich in omega-3 PUFA reduce the concentrations of 2-series PG and increase the synthesis of 3-series PG (e.g., PGE(3)), which are believed to be less inflammatory. However, studies on cellular consequences of increases in 3-series PG in comparison to 2-series PG have not been reported. In this study, we compared the effects of PGE(2) and PGE(3) on (i) cell proliferation in NIH 3T3 fibroblasts, (ii) expression and transcriptional regulation of the COX-2 gene in NIH 3T3 fibroblasts, and (iii) the production of an inflammatory cytokine, IL-6, in RAW 264.7 macrophages. PGE(3), unlike PGE(2), is not mitogenic to NIH 3T3 fibroblasts. PGE(2) and PGE(3) both induce COX-2 mRNA via similar signaling mechanisms; however, compared with PGE(2), PGE(3) is significantly less efficient in inducing COX-2 gene expression. Furthermore, although both PGE(2) and PGE(3) induce IL-6 synthesis in RAW 264.7 macrophages, PGE(3) is substantially less efficient compared with PGE(2). We further show that increasing the omega-3 content of membrane phospholipid results in a decrease in mitogen-induced PGE(2) synthesis. Taken together, our data suggest that successful replacement of omega-6 PUFA with omega-3 PUFA in cell membranes can result in a decreased cellular response to mitogenic and inflammatory stimuli.
欧米伽-6（ω-6）多不饱和脂肪酸（PUFA）在西方饮食中含量丰富，是包括2-系列前列腺素（PG）在内的多种关键炎症介质的前体。PGE₂是ω-6多不饱和脂肪酸花生四烯酸的环氧化酶（COX）代谢产物，是一种强效的炎症和细胞增殖介质。富含ω-3多不饱和脂肪酸的膳食补充剂可降低2-系列PG的浓度，并增加3-系列PG（如PGE₃）的合成，后者被认为炎症性较低。然而，与2-系列PG相比，关于3-系列PG增加对细胞影响的研究尚未见报道。在本研究中，我们比较了PGE₂和PGE₃对（i）NIH 3T3成纤维细胞增殖、（ii）NIH 3T3成纤维细胞中COX-2基因的表达和转录调控，以及（iii）RAW 264.7巨噬细胞中炎症细胞因子IL-6产生的影响。与PGE₂不同，PGE₃对NIH 3T3成纤维细胞无促有丝分裂作用。PGE₂和PGE₃均通过相似的信号机制诱导COX-2 mRNA；然而，与PGE₂相比，PGE₃诱导COX-2基因表达的效率显著较低。此外，虽然PGE₂和PGE₃均可诱导RAW 264.7巨噬细胞合成IL-6，但与PGE₂相比，PGE₃的效率要低得多。我们进一步表明，增加膜磷脂的ω-3含量会导致有丝分裂原诱导的PGE₂合成减少。综上所述，我们的数据表明，在细胞膜中用ω-3多不饱和脂肪酸成功替代ω-6多不饱和脂肪酸可导致细胞对有丝分裂原和炎症刺激的反应降低。
