Journal
BRAIN RESEARCH
Volume 1594, Issue -, Pages 27-35Publisher
ELSEVIER
DOI: 10.1016/j.brainres.2014.10.059
Keywords
Primary microglia; CXCL10; TNF; 2',3'-cAMP; 2'-AMP; 3'-AMP; Adenosine; Adenosine receptors; A(2A) receptors
Categories
Funding
- National Institutes of Health [NS087978, HD040686, HL109002, DK091190, HL069846, DK068575, DK079307]
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Background: Some cells, tissues and organs release 2',3'-cAMP (a positional isomer of 3',5'-cAMP) and convert extracellular 2',3'-cAMP to 2'-AMP plus 3'-AMP and convert these AMPs to adenosine (called the extracellular 2',3'-cAMP-adenosine pathway). Recent studies show that microglia have an extracellular 2',3'-cAMP-adenosine pathway. The goal of the present study was to investigate whether the extracellular 2',3'-cAMP-adenosine pathway could have functional consequences on the production of cytokines/chemokines by activated microglia. Methods: Experiments were conducted in cultures of primary murine microglia. In the first experiment, the effect of 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine on LPS-induced TNF-alpha and CXCL10 production was determined. In the next experiment, the first protocol was replicated but with the addition of 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX) (0.1 mu M; antagonist of adenosine receptors). The last experiment compared the ability of 2-chloro-N-6-cyclopentyladenosine (CCPA) (10 mu M; selective A(1) agonist), 5'-N-ethylcarboxamide adenosine (NECA) (10 mu M; agonist for all adenosine receptor subtypes) and CGS21680 (10 mu M; selective A(2A) agonist) to inhibit LPS-induced TNF-alpha and CXCL10 production. Results: (1) 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine similarly inhibited LPS-induced TNF-alpha and CXCL10 production; (2) DPSPX nearly eliminated the inhibitory effects of 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine on LPS-induced TNF-alpha and CXCL10 production; (3) CCPA did not affect LPS-induced TNF-alpha and CXCL10; (4) NECA and CGS21680 similarly inhibited LPS-induced TNF-alpha and CXCL10 production. Conclusions: 2',3'-cAMP and its metabolites (3'-AMP, 2'-AMP and adenosine) inhibit LPS-induced TNF-alpha and CXCL10 production via A(2A)-receptor activation. Adenosine and its precursors, via A(2A) receptors, likely suppress TNF-alpha and CXCL10 production by activated microglia in brain diseases. (C) 2014 Elsevier B.V. All rights reserved.
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