Abstract
First described for their metabolic and immunosuppressive effects, glucocorticoids are widely prescribed in clinical settings of inflammation. However, glucocorticoids are also potent inducers of apoptosis in many cell types and tissues. This review will focus on the established mechanisms of glucocorticoid-induced apoptosis and outline what is known about the apoptotic response in cells and tissues of the body after exposure to glucocorticoids. Glucocorticoid-induced apoptosis affects the skeletal system, muscular system, circulatory system, nervous system, endocrine system, reproductive system, and the immune system. Interestingly, several cell types have an anti-apoptotic response to glucocorticoids that is cytoprotective. Lastly, we will discuss the pro- and anti-apoptotic effects of glucocorticoids in cancers and their clinical implications.
Highlights
Glucocorticoids are essential for life [1], and their metabolic and immunosuppressive effects have been well established
Wistar rats that were injected with dexamethasone for five consecutive days experienced endothelial cell apoptosis that likely contributed to capillary structural rarefaction, which is associated with hypertension in animals and humans [24]
Many of the negative side effects of glucocorticoid therapy, such as cataracts, glaucoma, skin atrophy, hypertension, muscle wasting, diabetes mellitus, and thymus atrophy, can be attributed to the transactivation of the glucocorticoid receptor and subsequent gene induction [120]. This has led to research focusing on improved therapies for inflammatory diseases with selective glucocorticoid receptor modulators (SGRMs) or 3GLVVRFLDWLYHligands that permit GR transrepression of pro-inflammatory genes but are suggested to have less transactivation activity [120]
Summary
Glucocorticoids are essential for life [1], and their metabolic and immunosuppressive effects have been well established. Glucocorticoid signaling increases the expression of the pro-apoptotic Bcl-2 family member Bim, which can activate the pro-apoptotic proteins Bax/Bak to disrupt mitochondrial membrane potential, resulting in the release of cytochrome c and other apoptogenic proteins [9]. This leads to caspase 9 activation and subsequent effector caspase 3 activation and apoptosis [4,9]. Down regulation of anti-apoptotic proteins such as Bcl-2 or Bcl-xL [8] This balance of the pro- and anti-apoptotic proteins can be altered by glucocorticoids, and whether a pro-apoptotic or anti-apoptotic effect is induced is often tissue- and/or cell type-specific (See Figure 2)
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