The A2A receptor mediates an endogenous regulatory pathway of cytokine expression in THP-1 cells

Khaled Bshesh, Bin Zhao, Donn Spight, Italo Biaggioni, Igor Feokistov, Alvin Denenberg, Hector R. Wong, Thomas P. Shanley

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

Adenosine is an endogenous nucleoside that regulates numerous cellular functions including inflammation. Adenosine acts via cell-surface receptors subtyped as Al, A2A, A2B, and A3. The A2A receptor (A2AR) has been linked to anti-inflammatory effects of adenosine. Furthermore, microarray analysis revealed increased A2AR mRNA in lipopolysaccharide (LPS)-stimulated monocytes. We hypothesized that endogenous adenosine inhibited LPS-mediated tumor necrosis factor (TNF) production via A2AR stimulation. Using THP-1 cells, our results demonstrated that LPS increased expression of cellular A2AR and adenosine. A2AR agonism with 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamido adenosine (CGS 21680) after LPS decreased TNF production in a dose- and time-dependent manner, whereas A2AR antagonism significantly increased TNF and blocked the inhibitory effect of CGS 21680. This inhibitory pathway involved A2AR stimulation of cyclic adenosine monophosphate (cAMP) to activate protein kinase A, resulting in phosphorylation of cAMP response element-binding protein (CREB). Phospho-CREB had been shown to inhibit nuclear factor-κB transcriptional activity, as was observed with CGS 21680 treatment. Thus, following immune activation with LPS, endogenous adenosine mediates a negative feedback pathway to modulate cytokine expression in THP-1 cells.

Original languageEnglish (US)
Pages (from-to)1027-1036
Number of pages10
JournalJournal of Leukocyte Biology
Volume72
Issue number5
StatePublished - Nov 1 2002

Keywords

  • Adenosine
  • CREB
  • NF-KB
  • TNF

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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