Guay Jocelyne, Bateman Kevin, Gordon Robert, Mancini Joseph, Riendeau Denis
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec H9H 3L1, Canada.
J Biol Chem. 2004 Jun 4;279(23):24866-72. doi: 10.1074/jbc.M403106200. Epub 2004 Mar 24.
Peripheral inflammation involves an increase in cyclooxygenase-2 (COX-2)-mediated prostaglandin (PG) synthesis in the central nervous system (CNS), which contributes to allodynia and hyperalgesia. In the present study we have determined the changes in prostanoid tissue levels and in expression of terminal prostanoid synthases in both the CNS and inflamed peripheral tissue during carrageenan-induced paw inflammation in the rat. Prostanoid levels were measured by liquid chromatography-mass spectrometry and enzyme expression at the RNA level by quantitative PCR analysis during both the early (1-6 h) and late (12 and 24 h) phases of the inflammatory response. In the paw, the early phase was associated with increases in PGE(2) and thromboxane (TX)B(2) levels and with a peak of COX-2 expression that preceded that of microsomal prostaglandin-E(2) synthase-1 (mPGES-1). COX-2 and mPGES-1 remained elevated during the late phase, and PGE(2) continued to further increase through 24 h. The cytosolic PGE(2) synthase (cPGES) showed a small transient increase during the early phase, whereas mPGES-2 expression was not affected by inflammation. In the cerebrospinal fluid, elevated levels of PGE(2), 6-keto-PGF(1alpha), PGD(2), and TXB(2) were detected during the early phase. PGE(2) levels also increased in the spinal cord and, to a lesser extent, in the brain and remained elevated in both the cerebrospinal fluid and the spinal cord during the late phase. The expression of mPGES-1 was strongly up-regulated in the brain and spinal cord during inflammation, whereas no change was detected for the expression of cPGES, mPGES-2, COX-1, and terminal PGD, TX, or PGI synthases. The results show that the carrageenan-induced edema in the paw elicits an early phase of COX-2 induction in the CNS leading to an increase synthesis in PGD(2), 6-keto-PGF(1alpha), and TXB(2) in addition to the major PGE(2) response. The data also indicate that the up-regulation of mPGES-1 contributes to COX-2-mediated PGE(2) production in the CNS during peripheral inflammation.
外周炎症涉及中枢神经系统（CNS）中环氧合酶-2（COX-2）介导的前列腺素（PG）合成增加，这会导致痛觉过敏和痛觉超敏。在本研究中，我们确定了在角叉菜胶诱导的大鼠爪部炎症过程中，CNS和炎症外周组织中前列腺素类组织水平的变化以及末端前列腺素合酶的表达变化。在炎症反应的早期（1 - 6小时）和晚期（12和24小时），通过液相色谱 - 质谱法测量前列腺素类水平，并通过定量PCR分析在RNA水平上检测酶表达。在爪部，早期阶段与PGE(2)和血栓素（TX）B(2)水平升高以及COX-2表达峰值相关，该峰值先于微粒体前列腺素-E(2)合酶-1（mPGES-1）的峰值。在晚期阶段，COX-2和mPGES-1仍然升高，并且PGE(2)在24小时内持续进一步增加。胞质PGE(2)合酶（cPGES）在早期阶段显示出小的短暂增加，而mPGES-2的表达不受炎症影响。在脑脊液中，在早期阶段检测到PGE(2)、6-酮-PGF(1α)、PGD(2)和TXB(2)水平升高。PGE(2)水平在脊髓中也增加，在大脑中增加程度较小，并且在晚期阶段在脑脊液和脊髓中均保持升高。在炎症期间，mPGES-1的表达在大脑和脊髓中强烈上调，而未检测到cPGES、mPGES-2、COX-1以及末端PGD、TX或PGI合酶的表达变化。结果表明，角叉菜胶诱导的爪部水肿在CNS中引发了COX-2诱导的早期阶段，除了主要的PGE(2)反应外，还导致PGD(2)、6-酮-PGF(1α)和TXB(2)合成增加。数据还表明，mPGES-1的上调有助于外周炎症期间CNS中COX-2介导的PGE(2)产生。
