Elsevier

Biochemical Pharmacology

Volume 59, Issue 6, 15 March 2000, Pages 597-603
Biochemical Pharmacology

Commentary
Therapeutically targeting lymphocyte energy metabolism by high-dose glucocorticoids

https://doi.org/10.1016/S0006-2952(99)00273-7Get rights and content

Abstract

Lymphocytes use a considerable amount of energy, mainly in the form of ATP, especially when they become stimulated following activation by antibodies or mitogens. Cellular respiration is the major energy source, and in quiescent cells the ATP produced is used to drive protein synthesis and sodium transport. In stimulated cells there is significantly higher ATP production to balance the higher ATP demand of specific processes resulting from activation. The major ATP-consuming processes under these conditions are protein synthesis and Na+,K+-ATPase (about 20% each), while Ca2+-ATPase and RNA/DNA syntheses contribute about 10% each. There is a wealth of available information about glucocorticoid effects on lymphocytes, but here we focus on the extent to which this lymphocyte bioenergetic machinery is targeted by glucocorticoids when they are used therapeutically at high doses. High-dose glucocorticoids have been shown recently to interfere with processes that are essential for the activation and maintenance of lymphocytes, such as sodium and potassium transport. Therefore, in this article we describe the bioenergetics of lymphocytes in resting, activated, and glucocorticoid-treated states and present a concept for discussion to describe the relationship among these states in fundamental and clinical terms.

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.

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