Fiebich B L, Biber K, Lieb K, van Calker D, Berger M, Bauer J, Gebicke-Haerter P J
Abt. Psychiatrie, Universität Freiburg, Germany.
Glia. 1996 Oct;18(2):152-60. doi: 10.1002/(SICI)1098-1136(199610)18:2<152::AID-GLIA7>3.0.CO;2-2.
We investigated the regulation of COX-2 expression and activity by adenosine receptors in rat microglial cells. The selective adenosine A2a-receptor agonist CGS21680 and the non-selective adenosine A1- and A2-receptor agonist 5'-N-ethylcarboxiamidoadenosine (NECA) induced an increase in COX-2 mRNA levels and the synthesis of prostaglandin E2 (PGE2). The adenosine A1-receptor agonist cyclopentyladenosine (CPA) was less potent, and the adenosine A1-receptor-specific agonist N6-2-(-aminophenylo)ethyladenosine (APNEA) showed only marginal effects. Microglia expressed adenosine A1-, A2a-, and A3-, but not A2b-receptor mRNAs, whereas astroglial cells expressed adenosine A2b- but not A2a-receptor mRNA. The adenosine A2a-receptor selective antagonist (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837) inhibited both CGS21680-induced COX-2 expression and PGE2 release. CGS21680-increased PGE2 levels were inhibited by dexamethasone, by the nonsteroidal antiinflammatory drug meloxicam, and by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536). CGS21680 and NECA both increased intracellular cAMP levels in microglial cells. Dibutyryl cAMP as well as forskolin induced the release of PGE2. The results strongly suggest that adenosine A2a-receptor-induced intracellular signaling events cause an up-regulation of the COX-2 gene and the release of PGE2. Apparently, the cAMP second messenger system plays a crucial role in COX-2 gene regulation in rat microglial cells. The results are discussed with respect to neurodegenerative disorders of the CNS such as Alzheimer's disease, in which activated microglia are critically involved and COX inhibitors may be of therapeutic benefit.
我们研究了大鼠小胶质细胞中腺苷受体对COX - 2表达和活性的调节作用。选择性腺苷A2a受体激动剂CGS21680和非选择性腺苷A1及A2受体激动剂5'-N - 乙基甲酰胺基腺苷（NECA）可诱导COX - 2 mRNA水平升高以及前列腺素E2（PGE2）的合成增加。腺苷A1受体激动剂环戊腺苷（CPA）的作用较弱，而腺苷A1受体特异性激动剂N6 - 2 -（-氨基苯基）乙基腺苷（APNEA）仅显示出微弱的作用。小胶质细胞表达腺苷A1、A2a和A3受体mRNA，但不表达A2b受体mRNA，而星形胶质细胞表达腺苷A2b受体mRNA，但不表达A2a受体mRNA。腺苷A2a受体选择性拮抗剂（E）-8 -（3,4 - 二甲氧基苯乙烯基）-1,3 - 二丙基 - 7 - 甲基黄嘌呤（KF17837）可抑制CGS21680诱导的COX - 2表达和PGE2释放。地塞米松、非甾体抗炎药美洛昔康以及腺苷酸环化酶抑制剂9 -（四氢 - 2 - 呋喃基）-9H - 嘌呤 - 6 - 胺（SQ22536）均可抑制CGS21680升高的PGE2水平。CGS21680和NECA均可增加小胶质细胞内的cAMP水平。二丁酰cAMP以及福斯可林均可诱导PGE2的释放。结果强烈表明，腺苷A2a受体诱导的细胞内信号转导事件导致COX - 2基因上调和PGE2释放。显然，cAMP第二信使系统在大鼠小胶质细胞的COX - 2基因调节中起关键作用。本文就中枢神经系统神经退行性疾病如阿尔茨海默病对这些结果进行了讨论，在这类疾病中，活化的小胶质细胞起着关键作用，COX抑制剂可能具有治疗益处。
