Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever
Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever
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DOI：
10.1523/jneurosci.21-08-02669.2001
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发表时间：
2001-04-15
影响因子：
5.3
通讯作者：
Kobayashi, S
中科院分区：
文献类型：
--
作者：
Yamagata, K;Matsumura, K;Kobayashi, S
发烧是由大脑中前列腺素 E-2 (PGE(2)) 升高引发的。然而，其升高的机制仍未得到解答。我们在此克隆了大鼠谷胱甘肽依赖性微粒体前列腺素E合酶（mPGES），这是PGE（2）生物合成的末端酶，并在腹腔注射热原脂多糖（LPS）后检查了其在大鼠脑中的诱导。在Northern印迹分析中，正常条件下mPGES mRNA在脑中表达较弱，但在注射LPS后2至4小时内明显诱导表达。原位杂交研究表明，LPS诱导的mPGES mRNA信号主要与整个脑区的脑血管有关，尤其是静脉或小静脉型血管。免疫组织化学研究表明，mPGES 样免疫反应性在脑内皮细胞的核周区域表达，这些细胞被鉴定为冯·维勒布兰德因子阳性细胞。此外，在内皮细胞的核周区域，mPGES 与环氧合酶-2 (COX-2) 共定位，COX-2 是产生 mPGES 底物 PGH(2) 所必需的酶。抑制 cyclooxygenase-2 活性会导致 CSF 中的 PGE(2) 水平和发热均受到抑制（Cao 等，1997），表明这两种酶在功能上存在联系，并且这种联系对于发热至关重要。这些结果表明，脑内皮细胞通过表达 COX-2 和 mPGES，在发烧期间 PGE(2) 的产生中发挥重要作用。
Fever is triggered by an elevation of prostaglandin E-2 (PGE(2)) in the brain. However, the mechanism of its elevation remains unanswered. We herein cloned the rat glutathione-dependent microsomal prostaglandin E synthase (mPGES), the terminal enzyme for PGE(2) biosynthesis, and examined its induction in the rat brain after intraperitoneal injection of pyrogen lipopolysaccharide (LPS). In Northern blot analysis, mPGES mRNA was weakly expressed in the brain under the normal conditions but was markedly induced between 2 and 4 hr after the LPS injection. In situ hybridization study revealed that LPS-induced mPGES mRNA signals were mainly associated with brain blood vessels, especially vein or venular-type ones, in the whole brain area. Immunohistochemical study demonstrated that mPGES-like immunoreactivity was expressed in the perinuclear region of brain endothelial cells, which were identified as von Willebrand factor-positive cells. Furthermore, in the perinuclear region of the endothelial cells, mPGES was colocalized with cyclooxygenase-2 (COX-2), which is the enzyme essential for the production of the mPGES substrate PGH(2). Inhibition of cyclooxygenase-2 activity resulted in suppression of both PGE(2) level in the CSF and fever (Cao et at., 1997), suggesting that the two enzymes were functionally linked and that this link is essential for fever. These results demonstrate that brain endothelial cells play an essential role in the PGE(2) production during fever by expressing COX-2 and mPGES.