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

Elizabeth A Newell; Jennifer L Exo; Jonathan D Verrier; Travis C Jackson; Delbert G Gillespie; Keri Janesko-Feldman; Patrick M Kochanek; Edwin K Jackson

doi:10.1016/j.brainres.2014.10.059

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

Journal article

Peer reviewed

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

Elizabeth A Newell, Jennifer L Exo, Jonathan D Verrier, Travis C Jackson, Delbert G Gillespie, Keri Janesko-Feldman, Patrick M Kochanek and Edwin K Jackson

Brain research, Vol.1594, pp.27-35

01/12/2015

DOI: 10.1016/j.brainres.2014.10.059

PMCID: PMC4262711

PMID: 25451117

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Abstract

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. 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) (0.1μM; antagonist of adenosine receptors). The last experiment compared the ability of 2-chloro-N6-cyclopentyladenosine (CCPA) (10μM; selective A1 agonist), 5′-N-ethylcarboxamide adenosine (NECA) (10μM; agonist for all adenosine receptor subtypes) and CGS21680 (10μM; selective A2A agonist) to inhibit LPS-induced TNF-α and CXCL10 production. (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. 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. •The 2′,3′-cAMP-adenosine pathway is: 2′,3′-cAMP→2′-AMP+3′-AMP→adenosine.•Microglia express a 2′,3′-cAMP-adenosine pathway.•The 2′,3′-cAMP-adenosine pathway inhibits LPS-induced cytokine release.•A2A receptorsmediate inhibition of cytokines by the 2′,3′-cAMP-adenosine pathway.•The 2′,3′-cAMP-adenosine-A2A receptor axis may regulate neuroinflammation.

CXCL10

Adenosine

Adenosine receptors

2′,3′-cAMP

3′-AMP

TNF

A2A receptors

Primary microglia

2′-AMP

Details

Title: Subtitle: 2′,3′-cAMP, 3′-AMP, 2′-AMP and adenosine inhibit TNF-α and CXCL10 production from activated primary murine microglia via A2A receptors
Creators: Elizabeth A Newell - Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Jennifer L Exo - Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Jonathan D Verrier - Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Travis C Jackson - Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Delbert G Gillespie - Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Keri Janesko-Feldman - Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Patrick M Kochanek - Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Edwin K Jackson - Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Resource Type: Journal article
Publication Details: Brain research, Vol.1594, pp.27-35
DOI: 10.1016/j.brainres.2014.10.059
PMID: 25451117
PMCID: PMC4262711
NLM abbreviation: Brain Res
ISSN: 0006-8993
eISSN: 1872-6240
Publisher: Elsevier B.V
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: NS087978, HD040686, HL109002, DK091190, HL069846, DK068575, DK079307
Language: English
Date published: 01/12/2015
Academic Unit: Critical Care; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984065735102771

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