cDNA microarray analysis reveals a nuclear factor-κB-independent regulation of macrophage function by adenosine

Zoltán H. Németh, S. Joseph Leibovich, Edwin A. Deitch, E. Sylvester Vizi, Csaba Szabó, György Haskó

    Research output: Contribution to journalArticle

    63 Scopus citations

    Abstract

    Adenosine is released into the extracellular space from nerve terminals and cells subjected to ischemic stress. This nucleoside modulates a plethora of cellular functions via occupancy of specific receptors. Adenosine is also an important endogenous regulator of macrophage function, because it suppresses the production of a number of proinflammatory cytokines by these cells. However, the mechanisms of this anti-inflammatory effect have not been well characterized. We hypothesized that adenosine may exert some of its anti-inflammatory effects by decreasing activation of the transcription factor nuclear factor-κB (NF-κB), because gene expression of most of the proinflammatory cytokines inhibited by adenosine is dependent on NF-κB activation. Using bacterial lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, we found that adenosine as well as adenosine receptor agonists decreased the production of tumor necrosis factor (TNF)-α, a typical NF-κB-regulated cytokine. This effect of adenosine was not due to an action on the process of TNF-α release, because adenosine suppressed also the intracellular levels of TNF-α. However, cDNA microarray analysis revealed that mRNA levels of neither TNF-α nor other cytokines were altered by adenosine in either LPS-activated or quiescent macrophages. In addition, although LPS induced expression of a number of other, noncytokine genes, including the adenosine A2b receptor, adenosine did not affect the expression of these genes. Furthermore, adenosine as well as adenosine receptor agonists failed to decrease LPS-induced NF-κB DNA binding, NF-κB promoter activity, p65 nuclear translocation, and inhibitory κB degradation. Together, our results suggest that the anti-inflammatory effects of adenosine are independent of NF-κB.

    Original languageEnglish (US)
    Pages (from-to)1042-1049
    Number of pages8
    JournalJournal of Pharmacology and Experimental Therapeutics
    Volume306
    Issue number3
    DOIs
    StatePublished - Sep 1 2003

    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmacology

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