Crosstalk between signal transduction and metabolism in macrophages: metabolic effects of MEK inhibition

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. Here, the metabolic profile associated with the MEK/ERK cascade in macrophages was studied and the effect of its inhibition on the specific metabolic pattern of lipopolysaccharide (LPS) stimulation was characterized. A [1,2-13C2]glucose tracer-based metabolomic approach was used to examine the metabolic flux distribution in these cells. 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 (Fru-2,6-P2) concentration. The oxidative and non-oxidative pentose phosphate pathways (PPP) and the ratio between them also decreased. However, tricarboxylic acid (TCA) cycle flux did not change significantly. LPS activation led to the opposite responses, although all these were suppressed by PD325901. However, LPS also induced a small decrease in PPP fluxes and an increase in glutamine consumption that were not affected by PD325901. We conclude that inhibition of the ERK1/2 cascade interferes with central metabolism, and this crosstalk between signal transduction and metabolism also occurs in the presence of LPS.