Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock

György Haskó, David G. Kuhel, Zoltán H. Németh, Jon G. Mabley, Robert F. Stachlewitz, László Virág, Zsolt Lohinai, Garry J. Southan, Andrew L. Salzman, Csaba Szabó

    Research output: Contribution to journalArticle

    210 Scopus citations

    Abstract

    Extracellular purines, including adenosine and ATP, are potent endogenous immunomodulatory molecules. Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or ischemia. In the present study, we investigated whether extracellular inosine can affect inflammatory/immune processes. In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-α, IL-1, IL-12, macrophage-inflammatory protein-1α, and IFN-γ, but failed to alter the production of the anti- inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by nucleoside transporters and was partially reversed by blockade of adenosine A1 and A2 receptors. Inosine inhibited cytokine production by a posttranscriptional mechanism. The activity of inosine was independent of activation of the p38 and p42/p44 mitogen-activated protein kinases, the phosphorylation of the c-Jun terminal kinase, the degradation of inhibitory factor κB, and elevation of intracellular cAMP. Inosine suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model. Taken together, inosine has multiple anti-inflammatory effects. These findings, coupled with the fact that inosine has very low toxicity, suggest that this agent may be useful in the treatment of inflammatory/ischemic diseases.

    Original languageEnglish (US)
    Pages (from-to)1013-1019
    Number of pages7
    JournalJournal of Immunology
    Volume164
    Issue number2
    DOIs
    StatePublished - Jan 15 2000

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

    Fingerprint Dive into the research topics of 'Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock'. Together they form a unique fingerprint.

  • Cite this

    Haskó, G., Kuhel, D. G., Németh, Z. H., Mabley, J. G., Stachlewitz, R. F., Virág, L., Lohinai, Z., Southan, G. J., Salzman, A. L., & Szabó, C. (2000). Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. Journal of Immunology, 164(2), 1013-1019. https://doi.org/10.4049/jimmunol.164.2.1013