Lipopolysaccharide induces macrophage migration via prostaglandin D2 and prostaglandin E2
Lipopolysaccharide induces macrophage migration via prostaglandin D2 and prostaglandin E2
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DOI：
10.1124/jpet.108.137992
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发表时间：
2008-08-01
影响因子：
3.5
通讯作者：
Hori, Masatoshi
中科院分区：
文献类型：
--
作者：
Tajima, Tsuyoshi;Murata, Takahisa;Hori, Masatoshi
脂多糖（LPS）产生伴随着引发巨噬细胞迁移的前列腺素（PGs）。我们评估了PGs在启动巨噬细胞迁移中的作用，特别关注PGD（2）和PGE（2）。在RAW264.7巨噬细胞中，环氧化酶（考克斯）-2抑制剂CAY 10404 [3-（4-甲磺酰基苯基）-4-苯基-5-三氟甲基异恶唑]在4 h（早期）完全抑制LPS介导的迁移，但在8 h（晚期）仅部分抑制迁移，表明存在PG依赖性和非依赖性途径。在早期阶段，LPS上调考克斯-2、造血PGD合成酶（H-PGDS）和微粒体PGE合成酶1的mRNA表达，显著增加PGD（2）和PGE（2）。Th2淋巴细胞表达的趋化因子受体同源分子（CRTH2）激动剂，DK-PGD（2）（13 - 14-二氢-15-酮-PGD（2））和EP 4激动剂，ONO-AE1 - 329（16-{3-甲氧基甲基}苯基-ω-四去甲-3，7-二硫前列腺素E-1），但不是D前列腺素类受体、E前列腺素类受体（EP）2或EP 3的选择性激动剂，刺激随机迁移（化学运动）。在CRTH2缺陷型和H-PGDS缺陷型小鼠的腹腔巨噬细胞中，LPS介导的迁移在迁移的早期或晚期均受到显著抑制。H-PGDS抑制剂HQL-79 [4-（二苯基甲氧基）-1-[3-（1H-四唑-5-基）丙基-哌啶]]在两个阶段部分抑制RAW 264.7巨噬细胞的迁移。这些结果表明PGD（2）/CRTH2通路在LPS介导的巨噬细胞迁移中的重要性。在迁移后期，LPS上调单核细胞趋化蛋白（MCP）-1mRNA。CC趋化因子受体（CCR 2）拮抗剂RS102895 [1'-[2-[4-（三氟甲基）苯基]乙基]-螺[4H-3，1-苯并恶嗪-4，4'-哌啶]-2（1H）-酮]可抑制晚期LPS介导的迁移，而不影响早期。ONO-AE1 - 329上调MCP-1 mRNA表达，而DK-PGD（2）无此作用。总之，LPS刺激的趋化性或趋化性，或两者，通过串联排列的PGD（2）和PGE（2）在巨噬细胞中发生;即，1)LPS刺激前列腺素信号传导，通过PGD（2）/CRTH2和PGE（2）/EP4信号传导途径启动早期迁移;和2）LPS导致MCP-1的诱导，其有助于通过PGE（2）/EP4途径的巨噬细胞的后期迁移。
Lipopolysaccharide (LPS) produces prostaglandins (PGs) concomitant to eliciting macrophage migration. We evaluated the role of PGs in initiating the migration of macrophages, especially focusing on PGD(2) and PGE(2). In RAW264.7 macrophages, cyclooxygenase (COX)-2 inhibitor, CAY10404 [3-(4-methylsulphonylphenyl)-4-phenyl- 5-trifluoromethylisoxazole], completely inhibited LPS-mediated migration at 4 h (early phase) but only partially inhibited the migration at 8 h (late phase), suggesting the presence of PG-dependent and -independent pathways. In the early phase, LPS up-regulated mRNA expressions of COX-2, hematopoietic PGD synthase (H-PGDS), and microsomal-PGE synthase 1, increasing PGD(2) and PGE(2) substantially. The chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes (CRTH2) agonist, DK-PGD(2) (13-14-dihydro-15-keto-PGD(2)), and the EP4 agonist, ONO-AE1-329 (16-{3-methoxymethyl} phenyl-omega-tetranor-3,7-dithiaprostaglandin E-1), but not selective agonists of D prostanoid receptor, E prostanoid receptor (EP) 2, or EP3, stimulated random migration (chemokinesis). In peritoneal macrophages from CRTH2-deficient and H-PGDS-deficient mice, LPS-mediated migration was significantly inhibited at either early or late phases of the migration. The H-PGDS inhibitor, HQL-79 [4-(diphenylmethoxy)-1-[3-(1H-tetrazol-5-yl) propyl-piperidine]], partially inhibited the migration of the RAW264.7 macrophage in both phases. These results suggest the importance of the PGD(2)/CRTH2 pathway in LPS-mediated migration of macrophages. In the late phase of migration, LPS up-regulated monocyte chemoattractant protein (MCP)-1 mRNA. The CC chemokine receptor (CCR2) antagonist, RS102895 [1'-[2-[4-(trifluoromethyl)phenyl]ethyl]-spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one], inhibited LPS-mediated migration in the late phase without affecting the early phase. ONO-AE1-329, but not DK-PGD(2), up-regulated MCP-1 mRNA. Taken together, LPS stimulation of chemokinesis or chemotaxis, or both, occurs in macrophages via PGD(2) and PGE(2) in tandem arrangement; i.e., 1) LPS stimulates prostaglandin signaling, initiating early migration through the PGD(2)/CRTH2 and PGE(2)/EP4 signaling pathways; and 2) LPS leads induction of MCP-1, which contributes to later phase migration of the macrophages through the PGE(2)/EP4 pathway.