Molecular and Cellular Biochemistry

, Volume 424, Issue 1–2, pp 69–78 | Cite as

Methionine and methionine sulfoxide treatment induces M1/classical macrophage polarization and modulates oxidative stress and purinergic signaling parameters

  • Lien M. dos Santos
  • Tatiane M. da Silva
  • Juliana H. Azambuja
  • Priscila T. Ramos
  • Pathise S. Oliveira
  • Elita F. da Silveira
  • Nathalia S. Pedra
  • Kennia Galdino
  • Carlus A. T. do Couto
  • Mayara S. P. Soares
  • Rejane G. Tavares
  • Roselia M. Spanevello
  • Francieli M. Stefanello
  • Elizandra Braganhol


Methionine is an essential amino acid involved in critical metabolic process, and regulation of methionine flux through metabolism is important to supply this amino acid for cell needs. Elevation in plasma methionine commonly occurs due to mutations in methionine-metabolizing enzymes, such as methionine adenosyltransferase. Hypermethioninemic patients exhibit clinical manifestations, including neuronal and liver disorders involving inflammation and tissue injury, which pathophysiology is not completely established. Here, we hypothesize that alterations in macrophage inflammatory response may contribute to deleterious effects of hypermethioninemia. To this end, macrophage primary cultures were exposed to methionine (1 mM) and/or its metabolite methionine sulfoxide (0.5 mM), and M1/proinflammatory or M2/anti-inflammatory macrophage polarization was evaluated. In addition, inflammation-related pathways including oxidative stress parameters, as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities; reactive oxygen species (ROS) production, and purinergic signaling, as ATP/ADP/AMPase activities, were investigated. Methionine and/or methionine sulfoxide induced M1/classical macrophage activation, which is related to proinflammatory responses characterized by increased iNOS activity and TNF-α release. Further experiments showed that treatments promoted alterations on redox state of macrophages by differentially modulated SOD and CAT activities and ROS levels. Finally, methionine and/or methionine sulfoxide treatment also altered the extracellular nucleotide metabolism, promoting an increase of ATPase/ADPase activities in macrophages. In conclusion, these findings contribute to better understand the participation of proinflammatory responses in cell injury observed in hypermethioninemic patients.


Methionine Methionine sulfoxide Macrophage polarization Oxidative stress Ectonucleotidases 



This study was supported by the Brazilian agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq—Universal Processo No. 454262/2014-0; No. 482055/2013-8), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS). T.M. da Silva, J.H. Azambuja, P.T. Ramos, N.S. Pedra, P.S. Oliveira, E.F. da Silveira,K. Galdino, C.A.T. do Couto were recipients of CNPq or CAPES fellowship.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Lien M. dos Santos
    • 1
  • Tatiane M. da Silva
    • 2
  • Juliana H. Azambuja
    • 1
    • 4
  • Priscila T. Ramos
    • 1
  • Pathise S. Oliveira
    • 2
  • Elita F. da Silveira
    • 3
  • Nathalia S. Pedra
    • 1
  • Kennia Galdino
    • 1
  • Carlus A. T. do Couto
    • 1
  • Mayara S. P. Soares
    • 1
  • Rejane G. Tavares
    • 2
  • Roselia M. Spanevello
    • 1
  • Francieli M. Stefanello
    • 2
  • Elizandra Braganhol
    • 4
  1. 1.Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas Farmacêuticas e de AlimentosUniversidade Federal de Pelotas (UFPel)PelotasBrazil
  2. 2.Laboratório de Biomarcadores, Centro de Ciências Químicas Farmacêuticas e de AlimentosUniversidade Federal de Pelotas (UFPel)PelotasBrazil
  3. 3.Departamento de Morfologia, Instituto de Ciências BiológicasUniversidade Federal de Rio Grande (FURG)Rio GrandeBrazil
  4. 4.Departamento de Ciências Básicas da SaúdeUniversidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA)Porto AlegreBrazil

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