title: 5'-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes.
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-alpha (TNF-alpha), 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 (IkappaBalpha) degradation, and nuclear factor kappaB (NFkappaB) 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.
authors.affiliation: División de Hepatología y Terapia Génica, Departamento de Medicina Interna, CIMA, Universidad de Navarra, Pamplona, Spain.
authors.forename: Henar
authors.initials: H
authors.lastname: Hevia
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.forename: María L
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.forename: M Ujue
authors.initials: MU
authors.lastname: Latasa
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Elena R
authors.initials: ER
authors.lastname: García-Trevijano
authors.forename: Matías A
authors.initials: MA
authors.lastname: Avila
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003839:Deoxyadenosines / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D012436:S-Adenosylmethionine / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology; D013872:Thionucleosides / Q000493:pharmacokinetics*
chemical_list: D000893:Anti-Inflammatory Agents; D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D013872:Thionucleosides; C008500:5'-methylthioadenosine; D012436:S-Adenosylmethionine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases