CommentaryTherapeutically targeting lymphocyte energy metabolism by high-dose glucocorticoids
Section snippets
ATP-producing and -consuming pathways
Metabolism can be conceptually divided into reactions that provide or use energy. Free energy is released by either glycolysis or respiration and then distributed to energy-requiring reactions using intermediates such as ATP or other nucleoside triphosphates. Glycolysis produces relatively small amounts of ATP. In contrast, cellular respiration (oxidation of fuel molecules to drive oxidative phosphorylation) is the major energy source in aerobic organisms. Oxidative phosphorylation is the
Mitochondrial proton leak
Not all mitochondrial oxygen consumption is coupled to ATP synthesis, since mitochondria show a significant passive permeability to protons (termed “proton leak”), which is not an artifact of mitochondrial isolation since it has been demonstrated in mitochondria within isolated cells [12]. It is interesting that, first, the proton leak is higher in smaller mammals [13] and, second, mitochondrial proton permeability and leak flux depend on thyroid hormones [14]. Mitochondrial proton leak is an
Energy metabolism of quiescent lymphocytes
The energy metabolism of quiescent lymphocytes is not very complex. In quiescent thymocytes of the rat, only 50% of the coupled oxygen consumption could be assigned to specific processes [7]. Oxygen is used mainly to drive mitochondrial proton leak and to provide ATP for protein synthesis and cation transport, whereas oxygen consumption to provide ATP for RNA/DNA syntheses, ATP-dependent proteolysis, and Ca2+-ATPase was not measurable (Table 1). The sink for the ATP produced by the remaining
Mitogenic activation of energy metabolism
Several signal-transducing pathways have been described for lymphocyte activation. Antigens, mitogens, and other ligands can initiate a complex cascade of transmembrane signalling events involving different second messenger systems. These include pathways dependent on phospholipase C, protein kinase C, tyrosine kinases, and perhaps reactive oxygen species 16, 17, 18. The lectin acts as a mitogen that preferentially activates T-cells. It stimulates the energy metabolism of thymocytes within
Glucocorticoid effects on energy metabolism
Glucocorticoids have profound anti-inflammatory and immunosuppressive actions when used therapeutically. The therapeutic dose is quite variable and depends on the disease, but ranges from very low (e.g. basal immunosuppressive low-dose treatment in autoimmune diseases) to extremely high (e.g. pulse therapy used to treat flares of autoimmune diseases). In general, the more severe the underlying disorder, the higher the dose of glucocorticoids.
What is the rationale for the use of various dosage
Clinical implications
We would like to give our personal view of the whole story of quiescent, stimulated, and glucocorticoid-treated lymphocytes by using a descriptive model that summarises and interprets in clinical terms (Fig. 2). At first glance the figure may look rather complicated, but what is its message?
Lymphocytes artificially stimulated by the mitogen Con A (left y-axis) are equated bioenergetically to those that become activated during the pathogenesis of (auto)immunologically mediated diseases (right
Open questions
Of course, there are important questions open for further investigating high-dose glucocorticoid therapy, and experimental effort is being made currently to solve them.
First, the mechanisms of nongenomic effects of glucocorticoids need to be defined further. This would include the detection and cloning of the proposed membrane receptors as well as the definition of the physico-chemical interaction of high-dose glucocorticoids with membranes.
A second issue that is being examined currently in
Conclusions
Lymphocytes require sufficient energy to maintain cellular integrity and basal metabolism. This energy supply is crucial for lymphocytes that enter the activated state following stimulation by antibodies and lectins, when a significantly increased ATP requirement for cation transport and macromolecule synthesis becomes evident. In addition to their well-known genomic effects, high doses of glucocorticoids interfere, via nongenomic pathways, with processes of energy metabolism crucial for the
Acknowledgements
This work was supported by grants from the Deutsche Forschungsgemeinschaft (Bu 1015/1–1), Deutscher Akademischer Austauschdienst (D/96/17655), and Boehringer Ingelheim Fonds to F.B.
References (37)
- et al.
Regulation of lymphocyte activation by the cell-surface molecule CD22
Immunol Today
(1994) - et al.
The causes and functions of mitochondrial proton leak
Biochim Biophys Acta
(1994) - et al.
On the nature of the mitochondrial proton leak
Biochim Biophys Acta
(1991) - et al.
The quantitative contributions of mitochondrial proton leak and ATP turnover reactions to the changed respiration rates of hepatocytes from rats of different thyroid status
J Biol Chem
(1993) - et al.
Transmembrane signalling in T cells
Immunol Today
(1992) - et al.
Redox regulation of the mitogen-activated protein kinase pathway during lymphocyte activation
Biochim Biophys Acta
(1997) - et al.
Effects of the mitogen Concanavalin A on pathways of thymocyte energy metabolism
Biochim Biophys Acta
(1999) - et al.
The mechanism of stimulation of respiration by fatty acids in isolated hepatocytes
J Biol Chem
(1990) Monovalent ion transport and membrane potential changes during leukocyte activation
Cytosolic calcium changes during T- and B-lymphocyte activationBiological consequences and significance
Phosphoinositide metabolism in lymphocyte activation
Glucocorticoids and immune functionUnknown dimensions and new frontiers
Immunol Today
In vitro effects of glucocorticoid on mitochondrial energy metabolism
Biochim Biophys Acta
Equivalent doses and relative drug potencies for non-genomic glucocorticoid effects. A novel glucocorticoid hierarchy
Biochem Pharmacol
The role of protein tyrosine phosphatases in lymphocyte activation and differentiation
Crit Rev Immunol
T cell antigen receptor signal transduction pathways
Annu Rev Immunol
Cellular energy utilization and molecular origin of standard metabolic rate in mammals
Physiol Rev
Quantification of ATP-producing and consuming processes in quiescent pig spleen lymphocytes
Biochem Int
Cited by (21)
Effect of corticosteroids on viability and proliferation of the rainbow trout monocyte/macrophage cell line, RTS11
2002, Fish and Shellfish ImmunologyA high-dose pulse steroid regimen for controlling active chronic graft-versus-host disease
2001, Biology of Blood and Marrow TransplantationBioenergetics of t cell activation and death in HIV type 1 infection
2012, AIDS Research and Human RetrovirusesThe role of high-dose corticosteroids in the treatment of chronic lymphocytic leukemia
2012, Expert Opinion on Investigational Drugs