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PMID: 14522842 Published · ppublish English Comparative Study Journal Article Research Support, U.S. Gov't, P.H.S.

Oxidized ATP (oATP) attenuates proinflammatory signaling via P2 receptor-independent mechanisms.

British journal of pharmacology ·Vol. 140 ·No. 3 ·2003-10-00 ·Pages 507-19

Beigi RD, Kertesy SB, Aquilina G, Dubyak GR

Abstract

Periodate-oxidized ATP (oATP), which covalently modifies nucleotide-binding proteins, can significantly attenuate proinflammatory signaling. Although the P2X7 nucleotide receptor (P2X7R) is irreversibly antagonized by oATP, it is unclear whether anti-inflammatory actions of oATP are predominantly mediated via its actions on P2X7R. Here, we describe inhibitory effects of oATP on proinflammatory responses in three human cell types that lack expression of P2X7R: human umbilical vein endothelial cells (HUVEC), HEK293 cells, and 1321N1 astrocytes. oATP decreased by 40-70% the secretion of interleukin (IL)-8 stimulated by tumor necrosis factor-alpha (TNF-alpha) in all three cell types, by IL-1beta in HUVEC and 1321N1 cells, and by endotoxin in HUVEC. Attenuation of TNF-alpha-stimulated IL-8 secretion by oATP was similar in wild-type HEK cells or HEK cells stably expressing recombinant P2X7R. oATP also attenuated cytokine-stimulated expression of nuclear factor-kappaB-luciferase reporter genes expressed in HEK or 1321N1 cells, but did not affect the rapid downregulation of IkappaB. oATP had no effect on uridine triphosphate-induced activation of native P2Y2 receptors in HEK cells, but reduced the potency and efficacy of ADP as an agonist of native P2Y1 receptors. However, inhibition of P2Y1 receptors with the specific antagonist MRS2216 did not mimic the effects of oATP on TNF-alpha-stimulated IL-8 secretion. Although 1321N1 astrocytes lack expression of any known P2 receptor subtypes, oATP markedly inhibited ecto-ATPase activity in these cells, resulting in a significant accumulation of extracellular ATP. In summary, oATP can attenuate proinflammatory signaling by mechanisms independent of the expression or activation of known P2 receptor subtypes.

MeSH Terms
Adenosine Triphosphate/analogs & derivatives,metabolism,physiology Cell Line Cell Line, Tumor Cytokines/metabolism Humans Inflammation/metabolism Inflammation Mediators/pharmacology,physiology Oxidation-Reduction Purinergic P2 Receptor Agonists Receptors, Purinergic P2/metabolism Signal Transduction/drug effects,physiology
Chemicals
Cytokines Inflammation Mediators Purinergic P2 Receptor Agonists Receptors, Purinergic P2 2',3'-dialdehyde ATP Adenosine Triphosphate
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Beigi Reza D
Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
Kertesy Sylvia B
Aquilina Gretchen
Dubyak George R
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Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1038/sj.bjp.0705470
Published
2003-10-00
Pages
507-19
Language
English
Region
England
NLM ID
7502536
PMCID
PMC1574058
Subset
IM
Grants
NHLBI NIH HHS · P01 HL018708 · United States
NIGMS NIH HHS · R01 GM036387 · United States
Corrections
CommentIn
PMID: 14522840
External Links
PubMed source DOI: 10.1038/sj.bjp.0705470 PMC Full Text View journal details
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