Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin E synthase-1
Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin E synthase-1
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DOI：
10.1074/jbc.m400199200
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发表时间：
2004-08-06
影响因子：
4.8
通讯作者：
Kudo, I
中科院分区：
文献类型：
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作者：
Kamei, D;Yamakawa, K;Kudo, I
我们使用 mPGES-1 敲除 (KO) 小鼠检查了膜结合前列腺素 E 合酶 (mPGES)-1（PGE(2) 生物合成途径中的一种末端酶）的体内作用。 mPGES-1 KO 和野生型 (WT) 小鼠组织膜部分 PGES 活性的比较表明，mPGES-1 占 WT 小鼠中脂多糖 (LPS) 诱导型 PGES 的大部分。在 mPGES-1 缺失的巨噬细胞中，LPS 刺激的 PGE(2) 生成（而非其他 PG）显着受损，但环加氧酶 2 依赖性 PGE(2) 生成仍保持低水平。通过乙酸扭体反应评估，KO 小鼠的疼痛伤害感受相对于 WT 小鼠显着降低。当这些小鼠用LPS引发时，这种表型尤其明显，其中KO小鼠的伸展行为和腹膜PGE(2)水平远低于WT小鼠。与 WT 小鼠相比，KO 小鼠皮下植入棉线诱导的炎症肉芽组织的形成和伴随的背部血管生成显着减少。此外，胶原蛋白抗体诱导的关节炎（人类类风湿性关节炎模型）在 KO 小鼠中比在 WT 小鼠中症状更轻。总的来说，我们目前的结果提供了明确的证据，表明 mPGES-1 有助于形成参与疼痛过敏和炎症的 PGE(2)。
We examined the in vivo role of membrane-bound prostaglandin E synthase (mPGES)-1, a terminal enzyme in the PGE(2)-biosynthetic pathway, using mPGES-1 knockout (KO) mice. Comparison of PGES activity in the membrane fraction of tissues from mPGES-1 KO and wild-type (WT) mice indicated that mPGES-1 accounted for the majority of lipopolysaccharide (LPS)-inducible PGES in WT mice. LPS-stimulated production of PGE(2), but not other PGs, was impaired markedly in mPGES-1-null macrophages, although a low level of cyclooxygenase-2-dependent PGE(2) production still remained. Pain nociception, as assessed by the acetic acid writhing response, was reduced significantly in KO mice relative to WT mice. This phenotype was particularly evident when these mice were primed with LPS, where the stretching behavior and the peritoneal PGE(2) level of KO mice were far less than those of WT mice. Formation of inflammatory granulation tissue and attendant angiogenesis in the dorsum induced by subcutaneous implantation of a cotton thread were reduced significantly in KO mice compared with WT mice. Moreover, collagen antibody-induced arthritis, a model for human rheumatoid arthritis, was milder in KO mice than in WT mice. Collectively, our present results provide unequivocal evidence that mPGES-1 contributes to the formation of PGE(2) involved in pain hypersensitivity and inflammation.