Glucocorticoid-induced apoptosis of healthy and malignant lymphocytes

Abstract

Glucocorticoids exert a wide range of physiological effects, including the induction of apoptosis in lymphocytes. The progression of glucocorticoid-induced apoptosis is a multi-component process requiring contributions from both genomic and cytoplasmic signaling events. There is significant evidence indicating that the transactivation activity of the glucocorticoid receptor is required for the initiation of glucocorticoid-induced apoptosis. However, the rapid cytoplasmic effects of glucocorticoids may also contribute to the glucocorticoid-induced apoptosis-signaling pathway. Endogenous glucocorticoids shape the T-cell repertoire through both the induction of apoptosis by neglect during thymocyte maturation and the antagonism of T-cell receptor (TCR)-induced apoptosis during positive selection. Owing to their ability to induce apoptosis in lymphocytes, synthetic glucocorticoids are widely used in the treatment of haematological malignancies. Glucocorticoid chemotherapy is limited, however, by the emergence of glucocorticoid resistance. The development of novel therapies designed to overcome glucocorticoid resistance will dramatically improve the efficacy of glucocorticoid therapy in the treatment of haematological malignancies.

Fig. 1

Pleitrophic effects of glucocorticoids in responsive tissues. Endogenous glucocorticoids are generated in response to various stressors, including emotion and nociception. The subsequent physiolgical actions of glucocorticoids in responsive tissues are denoted as stimulatory (dashed line) or inhibitory (dotted line); (adapted from Rhen and Cidlowski, 2005).

Fig. 2

Domain structure of human glucocorticoid receptor (GR) protein. The GR contains three major functional regions: the N-terminal transactivation domain, the central DNA-binding domain and the C-terminal ligand-binding domain.

Fig. 3

The glucocorticoid receptor (GR): one gene yields many proteins. (a and b) The hGR pre-mRNA undergoes alternative splicing, generating the dominant GRα isoform and the lower abundance GRβ, GRγ, GR-A and GR-P isoforms. (c) The GRα isoform is also subject to alternative translation initiation, giving rise to translational isoforms differing in the length of the N-terminal domain.

Fig. 4

Mechanisms of glucocorticoid-regulated gene expression. Ligand binding liberates the glucocorticoid receptor (GR) from cytosolic sequestration, leading to rapid nuclear translocation and homodimerization. In the nucleus, GR can activate gene transcription through direct binding to GREs in the DNA or through stimulatory interactions with transcription factors such as STAT5. GR can also repress gene expression by directly interacting with nGREs in the DNA, or through inhibitory protein–protein interactions with transcription factors including NF-κB.

Fig. 5

Glucocorticoid-induced apoptosis signaling cascade. In this abbreviated model, glucocorticoids regulate the expression of apoptosis-effector genes, namely the pro-apoptotic Bcl-2 family member, Bim. Bim transactivation leads to the activation of downstream apoptotic mediators, Bax and Bak. Upon activation, Bax and Bak mediate disruption of the mitochondrial membrane potential and the subsequent release of cytochrome c and Apaf-1 into the cytosol. Apaf-1 and cytochrome c release leads to the activation of caspase 9, the subsequent activation of downstream effector caspases and the execution of glucocorticoid-induced apoptosis. The mitochondria is also responsible for some of the rapid, glucocorticoid-mediated cytoplasmic effects including calcium mobilization and the production of reactive oxygen species and ceramide, all of which may contribute to the progression of glucocorticoid-induced apoptosis.