Activation of adenosine receptors inhibits tumor necrosis factor-α release by decreasing TNF-α mRNA stability and p38 activity

Julie A. Fotheringham, Michael B. Mayne, Jeffrey A. Grant, Jonathan D. Geiger

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Adenosine receptor agonists have anti-inflammatory properties and modulate immune responses partly by inhibiting pro-inflammatory cytokine production by monocytes. We investigated signal transduction mechanisms by which adenosine receptor activation inhibits tumor necrosis factor-α (TNF-α) production. Phorbol-12-myristate-13-acetate (PMA) and phytohemagglutinin treatment of human pro-monocytic U937 cells increased TNF-α protein release. Activation of adenosine receptors up to 1 hr following stimulation with PMA/phytohemagglutinin significantly inhibited TNF-α protein release indicating that inhibition of TNF-α occurred post-transcriptionally. The adenosine receptor agonist 2-p-(carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) decreased stability and half-life of PMA/phytohemagglutinin-induced TNF-α mRNA from 80 to 37 min. p38 signaling pathways control TNF-α mRNA stability in macrophages and we confirmed in our cells that p38 was involved in controlling TNF-α release post-transcriptionally. Activation of adenosine receptors with CGS 21680 decreased phospho-p38 protein levels. These data suggest that adenosine receptor activation regulates TNF-α release post-transcriptionally by decreasing mRNA stability through a mechanism involving inhibition of p38 activity.

Original languageEnglish (US)
Pages (from-to)87-95
Number of pages9
JournalEuropean Journal of Pharmacology
Volume497
Issue number1
DOIs
StatePublished - Aug 16 2004

Keywords

  • Adenosine
  • Monocyte
  • TNF-α
  • mRNA stability
  • p38

ASJC Scopus subject areas

  • Pharmacology

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