Bioenergetics of Human Peripheral Blood Mononuclear Cell Metabolism in Quiescent, Activated, and Glucocorticoid-Treated States

Abstract

The first quantitative findings on the energy metabolism of human immune cells are presented. In quiescent peripheral blood mononuclear cells (PBMC) protein biosynthesis and Na+,K+-ATPase activity each accounted for 8% of cellular oxygen consumption. Stimulation with 25, 50, and 75 microg Con A/ml (1.25, 2.5 or 3.75 microg/10(6) cells) increased total oxygen consumption within seconds by 8, 36, and 53%, respectively. After addition of 75 microg Con A/ml, the proportion of cellular oxygen consumption due to protein biosynthesis, Na+,K+-ATPase activity, and Ca2+-ATPase activity was 15% each and that due to DNA/RNA synthesis was 8%. On the basis of these findings the immediate effects of five different glucocorticoids on cellular energy metabolism were investigated. The various glucocorticoids exerted basically the same inhibitory effects on Con A-stimulated cellular respiration and individual ATP-consuming processes, but differed significantly in potency. Similar to previous studies on rat thymocytes, the relative potencies of the glucocorticoids were found to be: prednylidene (1.7) > dexamethasone (1.5) > methylprednisolone (1.0) > prednisolone (0.3) > betamethasone (< 0.2). Given their rapidity of onset, these effects must be nongenomically mediated. The differences between the relative potencies of the various glucocorticoids for these effects and those for the classical genomic effects have important clinical implications, in particular for high-dose systemic and local glucocorticoid therapy.

Chorioamnionitis exposure remodels the unique histone modification landscape of neonatal monocytes and alters the expression of immune pathway genes

“…Suboptimal tissue gas exchange in hemoglobinopathies is thought to result in compensatory hemoglobin synthesis in different cell lineages, including monocytes [31]. Inflammation-associated immune cell activation causes increased oxygen consumption and cellular respiration, so it is possible that the chorioamnionitis-exposed monocytes are upregulating hemoglobinassociated transcripts in an attempt to compensate for this [32]. Both term and preterm fetuses exposed to chorioamnionitis can mount a systemic inflammatory response, resulting in elevated fetal cortisol levels and fetal immune cell activation with increased expression of the cytokines and chemokines IL-1b, IL-6, TNF-a, G-CSF, and CXCL1 [33][34][35][36][37].…”

Regulation of mammalian nucleotide metabolism and biosynthesis

“…This will require an increase in the number of ribosomes and thus rRNA, as well as the concomitant energy production needed to meet the enhanced demand for the highly endergonic nucleotide biosynthesis (7,13,51). However, it has been argued that the utilization for macromolecule biosynthesis is a small fraction of the total cellular adenosine triphosphate (ATP) consumption (52,53). Nevertheless, the ATP concentrations (and probably the more relevant ATP/ADP.Pi ratio which is the thermodynamic potential (54,55)) cannot fall below critical levels to maintain cell viability.…”

Glucocorticoids in the treatment of neonatal meconium aspiration syndrome

“…For example, assessing some rapid nongenomic effects, dexamethasone was shown to be the most potent among the tested GCs, thanks probably to the lowest lipophilicity facilitating its interaction directly with the cell membrane [9, 46, 64, 79]. …”