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Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice
Published on: March 10, 2017
5'-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes
Henar Hevia1, Marta Varela-Rey, Fernando J Corrales
1División de Hepatología y Terapia Génica, Departamento de Medicina Interna, CIMA, Universidad de Navarra, Pamplona, Spain.
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.
Insights
5'-methylthioadenosine (MTA) demonstrates significant anti-inflammatory effects by preventing lethal responses to bacterial lipopolysaccharide. This nucleoside suppresses key inflammatory mediators and pathways, offering potential for managing inflammatory diseases.
Area of Science:
- Immunology and Pharmacology
- Molecular Biology
Background:
- S-adenosylmethionine (AdoMet) influences inflammatory mediator production.
- 5'-methylthioadenosine (MTA) is a metabolite of AdoMet.
- The anti-inflammatory potential of MTA requires investigation.
Purpose of the Study:
- To evaluate the anti-inflammatory properties of 5'-methylthioadenosine (MTA).
- To investigate MTA's effects on inflammatory pathways in cellular and animal models.
Main Methods:
- MTA administration in bacterial lipopolysaccharide (LPS)-challenged mice.
- Treatment of murine macrophage RAW 264.7 cells and rat hepatocytes with MTA.
- Analysis of inflammatory mediator production, gene expression, and signaling pathway activation (MAPK, NF-κB).
Main Results:
- MTA administration prevented LPS-induced lethality in mice.
- MTA suppressed TNF-alpha and iNOS, while stimulating IL-10 in vivo and in vitro.
- MTA inhibited iNOS and COX2 induction, and key inflammatory signaling pathways including p38 MAPK and NF-κB.
Conclusions:
- 5'-methylthioadenosine (MTA) possesses significant immunomodulatory and anti-inflammatory properties.
- MTA's effects are independent of conversion to AdoMet or interaction with the cAMP pathway.
- MTA demonstrates therapeutic potential for managing inflammatory diseases.
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