title: Relevance of the MEK/ERK signaling pathway in the metabolism of activated macrophages: a metabolomic approach.
abstract: The activation of immune cells in response to a pathogen involves a succession of signaling events leading to gene and protein expression, which requires metabolic changes to match the energy demands. The metabolic profile associated with the MAPK cascade (ERK1/2, p38, and JNK) in macrophages was studied, and the effect of its inhibition on the specific metabolic pattern of LPS stimulation was characterized. A [1,2-[(13)C](2)]glucose tracer-based metabolomic approach was used to examine the metabolic flux distribution in these cells after MEK/ERK inhibition. Bioinformatic tools were used to analyze changes in mass isotopomer distribution and changes in glucose and glutamine consumption and lactate production in basal and LPS-stimulated conditions in the presence and absence of the selective inhibitor of the MEK/ERK cascade, PD325901. Results showed that PD325901-mediated ERK1/2 inhibition significantly decreased glucose consumption and lactate production but did not affect glutamine consumption. These changes were accompanied by a decrease in the glycolytic flux, consistent with the observed decrease in fructose-2,6-bisphosphate concentration. The oxidative and nonoxidative pentose phosphate pathways and the ratio between them also decreased. However, tricarboxylic acid cycle flux did not change significantly. LPS activation led to the opposite responses, although all of these were suppressed by PD325901. However, LPS also induced a small decrease in pentose phosphate pathway fluxes and an increase in glutamine consumption that were not affected by PD325901. We concluded that inhibition of the MEK/ERK cascade interferes with central metabolism, and this cross-talk between signal transduction and metabolism also occurs in the presence of LPS.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors.forename: Paqui G
authors.initials: PG
authors.lastname: Través
authors.forename: Pedro
authors.initials: P
authors.lastname: de Atauri
authors.forename: Silvia
authors.initials: S
authors.lastname: Marín
authors.forename: María
authors.initials: M
authors.lastname: Pimentel-Santillana
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Rodríguez-Prados
authors.forename: Igor
authors.initials: I
authors.lastname: Marín de Mas
authors.forename: Vitaly A
authors.initials: VA
authors.lastname: Selivanov
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
mesh_terms: D050260:Carbohydrate Metabolism; D019295:Computational Biology; D006019:Glycolysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D008660:Metabolism; D055432:Metabolomics / Q000379:methods*; D010427:Pentose Phosphate Pathway
chemical_list: D008070:Lipopolysaccharides