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Cyclooxygenase‐2 expression in rat microglia is induced by adenosine A 2a ‐receptors
Author(s) -
Fiebich Bernd L.,
Biber Knut,
Lieb Klaus,
Van Calker Dietrich,
Berger Mathias,
Bauer Joachim,
GebickeHaerter Peter J.
Publication year - 1996
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/(sici)1098-1136(199610)18:2<152::aid-glia7>3.0.co;2-2
Subject(s) - biology , adenosine , microglia , adenosine a2a receptor , cyclooxygenase , receptor , neuroscience , adenosine receptor , pharmacology , endocrinology , immunology , biochemistry , inflammation , enzyme , agonist
We investigated the regulation of COX‐2 expression and activity by adenosine receptors in rat microglial cells. The selective adenosine A 2a ‐receptor agonist CGS21680 and the non‐selective adenosine A 1 ‐ and A 2 ‐receptor agonist 5′‐N‐ethylcarboxi‐amidoadenosine (NECA) induced an increase in COX‐2 mRNA levels and the synthesis of prostaglandin E 2 (PGE 2 ). The adenosine A 1 ‐receptor agonist cyclopentyladenosine (CPA) was less potent, and the adenosine A 3 ‐receptor‐specific agonist N 6 ‐2‐(‐aminophenylo)ethyladenosine (APNEA) showed only marginal effects. Microglia expressed adenosine A 1 ‐, A 2a ‐, and A 3 ‐, but not A 2b ‐receptor mRNAs, whereas astroglial cells expressed adenosine A 2b ‐ but not A 2a ‐receptor mRNA. The adenosine A 2a ‐receptor selective antagonist (E)‐8‐(3,4‐dimethoxystyryl)‐1,3‐dipropyl‐7‐methylxanthine (KF17837) inhibited both CGS21680‐induced COX‐2 expression and PGE 2 release. CGS21680‐increased PGE 2 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 PGE 2 . The results strongly suggest that adenosine A 2a ‐receptor‐induced intracellular signaling events cause an up‐regulation of the COX‐2 gene and the release of PGE 2 . 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. © 1996 Wiley‐Liss, Inc.