Molecular mechanisms of glucocorticoid action and resistance

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Abstract

The actions of glucocorticoid hormones are mediated by an intracellular receptor, the glucocorticoid receptor (GR). The mechanism of action of this ligand-inducible transcription factor is discussed, focusing on mechanisms of glucocorticoid resistance. Three mechanisms are highlighted: ligand-induced down-regulation of the receptor, the dominant-negative inhibition by the β-isoform of the receptor, and repression by the transcription factor NF-κB. It has been shown that these mechanisms can significantly inhibit glucocorticoid signaling, and could therefore seriously decrease the efficacy of glucocorticoids used clinically.

Introduction

Glucocorticoids are used to treat a wide variety of inflammatory diseases, including allergies, asthma, rheumatoid arthritis, and auto-immune diseases. Glucocorticoids exert functions that are crucial for life, and therefore complete glucocorticoid resistance is uncommon. However, there is large variation in responsiveness to glucocorticoid therapy between individuals. In the present paper, we discuss several mechanisms of glucocorticoid resistance. The actions of glucocorticoids are mediated by an intracellular receptor, the glucocorticoid receptor (GR), a member of the nuclear receptor family of ligand-dependent transcription factors. Upon activation by their ligand, these receptors can act as transcription factors, i.e. they can alter the expression of specific target genes. We will first provide an overview of the mechanism of action of GR before discussing molecular mechanisms of glucocorticoid resistance.

Section snippets

Human GR gene

The human glucocorticoid receptor gene structure was elucidated in 1991 [1]. The gene is located on chromosome 5 and it consists of nine exons (as shown in Fig. 1A). Exon 1 and the first part of exon 2 contain the 5′UTR, exons 2–9 the coding sequences, and exon 9 the 3′UTR [1], [2]. Recently, the presence of two previously unidentified exons has been demonstrated (exon 1A and 1B) upstream from the originally defined exon 1 (which is now named exon 1C). At least three promoters regulate the

Homologous down-regulation

In several tissues and cultured cell lines, administration of a glucocorticoid receptor agonists results in a significant down-regulation of the expression of the GR. This has been demonstrated in vitro by whole cell ligand-binding assays in AtT-20 and HeLa cells, and cultured lymphocytes [88], [89], [90]. Similarly, down-regulation in vivo has been shown in the rat brain [91], [92] and in human lymphocytes [93]. Although the results vary, most studies show a decrease in receptor level of 50%

Conclusions

Several factors define the responsiveness of a cell to glucocorticoids. In the present paper, we have illustrated three mechanisms that can contribute to glucocorticoid resistance, and they are shown schematically in Fig. 2. During glucocorticoid treatment of an immune-related disease, these mechanisms may seriously harm the efficacy of the therapy. Pro-inflammatory signals have been shown to activate NF-κB and increase the expression level of hGRβ, which will result in decreased sensitivity to

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    Proceedings of the 15th International Symposium of the Journal of Steroid Biochemistry and Molecular Biology, “Recent Advances in Steroid Biochemistry and Molecular Biology”, Munich, Germany, 17–20 May 2002.

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