5′-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes

Authors

  • Henar Hevia,

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, CIMA, Universidad de Navarra, Pamplona, Spain
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    • H.H. and M.V.-R. contributed equally to this work. H.H. was supported by a fellowship from Fundacion Ramon Acreces.

  • Marta Varela-Rey,

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, CIMA, Universidad de Navarra, Pamplona, Spain
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    • H.H. and M.V.-R. contributed equally to this work. H.H. was supported by a fellowship from Fundacion Ramon Acreces.

  • Fernando J. Corrales,

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, CIMA, Universidad de Navarra, Pamplona, Spain
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  • Carmen Berasain,

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, CIMA, Universidad de Navarra, Pamplona, Spain
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  • María L. Martínez-Chantar,

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, CIMA, Universidad de Navarra, Pamplona, Spain
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  • M. Ujue Latasa,

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, CIMA, Universidad de Navarra, Pamplona, Spain
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  • Shelly C. Lu,

    Corresponding author
    1. Division of Gastroenterology and Liver Diseases, USC-UCLA, Research Center for Alcoholic Liver and Pancreatic Diseases, USC Liver Disease Research Center, USC School of Medicine, Los Angeles, CA
    • Keck School of Medicine USC, HMR 415, 2011 Zonal Ave., Los Angeles, CA 90033
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    • fax: 323-442-3234

  • José M. Mato,

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, CIMA, Universidad de Navarra, Pamplona, Spain
    Current affiliation:
    1. CIC-Biogune, Zamudio 48710, Bizkaia, Spain
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    • J.M.M., E.R.G.-T., and M.A.A. share senior authorship.

  • Elena R. García-Trevijano,

    Corresponding author
    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, CIMA, Universidad de Navarra, Pamplona, Spain
    • División de Hepatología y Terapia Génica, Departamento de Medicina Interna, FIMA, Facultad de Medicina, Universidad de Navarra, 31008 Pamplona, Spain
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    • J.M.M., E.R.G.-T., and M.A.A. share senior authorship.

    • fax: +34-948-425677

  • Matías A. Avila

    1. División de Hepatología y Terapia Génica, Departamento de Medicina Interna, CIMA, Universidad de Navarra, Pamplona, Spain
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    • J.M.M., E.R.G.-T., and M.A.A. share senior authorship.


  • Funded, in part, by the agreement between FIMA and the VTE project CIMA.

Abstract

5′-methylthioadenosine (MTA) is a nucleoside generated from S-adenosylmethionine (AdoMet) during polyamine synthesis. Recent evidence indicates that AdoMet modulates in vivo the production of inflammatory mediators. We have evaluated the anti-inflammatory properties of MTA in bacterial lipopolysaccharide (LPS) challenged mice, murine macrophage RAW 264.7 cells, and isolated rat hepatocytes treated with pro-inflammatory cytokines. MTA administration completely prevented LPS-induced lethality. The life-sparing effect of MTA was accompanied by the suppression of circulating tumor necrosis factor-α (TNF-α), inducible NO synthase (iNOS) expression, and by the stimulation of IL-10 synthesis. These responses to MTA were also observed in LPS-treated RAW 264.7 cells. MTA prevented the transcriptional activation of iNOS by pro-inflammatory cytokines in isolated hepatocytes, and the induction of cyclooxygenase 2 (COX2) in RAW 264.7 cells. MTA inhibited the activation of p38 mitogen-activated protein kinase (MAPK), c-jun phosphorylation, inhibitor kappa B alpha (IκBα) degradation, and nuclear factor κB (NFκB) activation, all of which are signaling pathways related to the generation of inflammatory mediators. These effects were independent of the metabolic conversion of MTA into AdoMet and the potential interaction of MTA with the cAMP signaling pathway, central to the anti-inflammatory actions of its structural analog adenosine. In conclusion, these observations demonstrate novel immunomodulatory properties for MTA that may be of value in the management of inflammatory diseases. (HEPATOLOGY 2004;39:1088–1098.)

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