ATP suppression of interleukin-12 and tumour necrosis factor-α release from macrophages

György Haskó, David G. Kuhel, Andrew L. Salzman, Csaba Szabó

    Research output: Contribution to journalArticle

    53 Scopus citations

    Abstract

    1. Immune cell activation releases ATP into the extracellular space. ATP-sensitive P2 purinergic receptors are expressed on immune cells and activation of these receptors alters immune cell function. Furthermore, ATP is metabolized by ectonucleotidases to adenosine, which has also been shown to alter cytokine production. In the present study, we investigated how extracellular ATP affects interleukin (IL)-12 and tumour necrosis factor (TNF)-α production in bacterial lipopolysaccharide (LPS)-treated murine peritoneal macrophages and we also examined whether extracellular ATP alters the production of the T helper 1 cytokine interferon (IFN)-γ. 2. Pretreatment of the peritoneal macrophages with ATP or various ATP analogues decreased both IL-12 and TNF-α production induced by LPS (10 μg ml-1). The effect of ATP was partially reversed by cotreatment with adenosine deaminase (0.1-1 u ml-1), suggesting that the suppressive effect of ATP on cytokine production is, in part, due to its degradation products. 3. Immunoneutralization with an anti-IL-10 antibody demonstrated that although ATP increases IL-10 production, the inhibition of IL-12 and TNF-α production is independent of the increased IL-10. 4. The effect of ATP was pretranslational, as it suppressed steady state levels of mRNAs for IL-12 (both p35 and p40). 5. In spleen cells stimulated with either LPS (10 μg ml-1) or anti-CD3 (2 μg ml-1) antibody, ATP suppressed, in a concentration-dependent manner, the production of IFN-γ. 6. These results suggest that extracellular ATP has multiple anti-inflammatory effects and that release of ATP into the extracellular space may play a role in blunting the overactive immune response in autoimmune diseases.

    Original languageEnglish (US)
    Pages (from-to)909-914
    Number of pages6
    JournalBritish Journal of Pharmacology
    Volume129
    Issue number5
    DOIs
    StatePublished - Jan 1 2000

    Keywords

    • ATP
    • Adenosine
    • Anti-CD3 antibody
    • Interleukin-10
    • Interleukin-12
    • Lipopolysaccharide
    • Nucleotide
    • Purinergic
    • T helper 1
    • T helper 2

    ASJC Scopus subject areas

    • Pharmacology

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