2. Academic Validation
  3. 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine inhibit TNF-α and CXCL10 production from activated primary murine microglia via A2A receptors

2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine inhibit TNF-α and CXCL10 production from activated primary murine microglia via A2A receptors

  • Brain Res. 2015 Jan 12;1594:27-35. doi: 10.1016/j.brainres.2014.10.059.
Elizabeth A Newell 1,  Jennifer L Exo 2,  Jonathan D Verrier 3,  Travis C Jackson 4,  Delbert G Gillespie 5,  Keri Janesko-Feldman 6,  Patrick M Kochanek 7,  Edwin K Jackson 8
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 2 Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 3 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 4 Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 5 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 6 Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 7 Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: [email protected].
  • 8 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: [email protected].
PMID: 25451117 DOI: 10.1016/j.brainres.2014.10.059
Abstract

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-α 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 μM; antagonist of adenosine receptors). The last experiment compared the ability of 2-chloro-N(6)-cyclopentyladenosine (CCPA) (10 μM; selective A1 agonist), 5'-N-ethylcarboxamide adenosine (NECA) (10 μM; agonist for all Adenosine Receptor subtypes) and CGS21680 (10 μM; selective A2A agonist) to inhibit LPS-induced TNF-α and CXCL10 production.

Results: (1) 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine similarly inhibited LPS-induced TNF-α and CXCL10 production; (2) DPSPX nearly eliminated the inhibitory effects of 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine on LPS-induced TNF-α and CXCL10 production; (3) CCPA did not affect LPS-induced TNF-α and CXCL10; (4) NECA and CGS21680 similarly inhibited LPS-induced TNF-α and CXCL10 production.

Conclusions: 2',3'-cAMP and its metabolites (3'-AMP, 2'-AMP and adenosine) inhibit LPS-induced TNF-α and CXCL10 production via A2A-receptor activation. Adenosine and its precursors, via A2A receptors, likely suppress TNF-α and CXCL10 production by activated microglia in brain diseases.

Keywords

2′,3′-cAMP; 2′-AMP; 3′-AMP; A(2A) receptors; Adenosine; Adenosine receptors; CXCL10; Primary microglia; TNF.

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