Molecular mechanisms of the glucocorticoid receptor in steroid therapy – lessons from transgenic mice

Abstract

Glucocorticoids (GCs) are potent anti-inflammatory agents that are used to treat chronic inflammatory diseases, allergic conditions, and some cancers. However, their therapeutic effects are hampered by severe side effects, such as muscle weakness, insulin resistance, fat redistribution, and osteoporosis. GCs act on many cell types that express the GC receptor (GR) via several modes of action. One of them includes GR homodimers recognizing binding sequences in the DNA of gene promoters. Another mode involves the modulation of other DNA-bound transcription factors via dimer-independent mechanisms. To what extent these mechanisms contribute to GC-mediated effects is currently being elucidated from analyses of mice with conditional and function-selective mutations of the GR and is summarized in this review. Whether GR homodimerization or its monomer activity is decisive in the therapeutic effectiveness and associated side effects of GCs for the treatment of inflammatory conditions depends on the type of the pathological condition. Thus, the classic criterion for selective GR modulators, discrimination between GR dimer- and GR monomer-dependent protein-protein interaction, will not help in any condition to avoid side effects and maintain anti-inflammatory activity. Rather, novel criteria for selective GR modulators have to be defined that take into consideration the tissue-specific mechanisms of the GR to achieve optimized anti-inflammatory therapies with reduced side effects. In the case of avoiding osteoporosis as a side effect, a first example of such optimized compounds can be provided.

The glucocorticoid receptor in inflammatory processes: transrepression is not enough

“…However, with the current notion of the role of the endogenous more complex GRE sequences as allosteric GR ligands, determining the transcriptional outcome (Meijsing et al, 2009), simple assays based on the consensus GRE sequence, likely do not suffice. Moreover, most were selected for their capacity to inhibit the pro-inflammatory TFs NF-κB and AP1 (Schacke et al, 2007), despite the growing list of immune-regulating TFs that are inhibited by GR, including NFAT, IRF3, CREB, T-bet and GATA3 (Hübner and Tuckermann, 2012).…”

“…These mice express a point mutant version of GR, where Alanine 465 is changed to a Threonine (A465T and in human GR A458T), located in the second zinc finger motif of the DBD, leading to reduced homodimerisation of the GR and subsequent reduced binding to GRE elements (Heck et al, 1994;Reichardt et al, 1998;Lim et al, 2015). Interfering with the dimerisation interface strongly abrogates the antiinflammatory actions of endogenous GCs, as GR dim mice are highly susceptible for several inflammatory disease models (Nixon et al, 2013;Vandevyver et al, 2013), such as TNF-and LPS-induced acute inflammation Tuckermann et al, 2007;Hübner and Tuckermann, 2012;Kleiman et al, 2012;Vandevyver et al, 2012a,b;Silverman et al, 2013) and CLP (cecal ligation and puncture)-induced sepsis Kleiman et al, 2012) (Table 1). In addition, GR dimerisationdependent actions are also indispensable in the protection by exogenous GCs during rheumatoid arthritis (Baschant et al, 2011;Baschant et al, 2012) and allergic contact dermatitis Tuckermann et al, 2007) (Table 1).…”

“…In addition to their potent anti-inflammatory properties, GCs are critical regulators of a wide variety of fundamental processes, including metabolic homeostasis, cell proliferation, development and reproduction. Owing to these metabolic actions of GCs, long-term GC treatment is unfortunately associated with various undesirable effects, such as diabetes, osteoporosis, glaucoma and muscle wasting Hübner and Tuckermann, 2012). These unwanted sideeffects, together with the occurrence of unresponsiveness to the beneficial effects of GCs, called GC resistance (GCR), constrain the therapeutic success of GCs (Vandevyver et al, 2014).…”

Dexamethasone mediates pancreatic cancer progression by glucocorticoid receptor, TGFβ and JNK/AP-1

“… 6 , 10 , 14 Glucocorticoids transduce their broad spectrum of activities by binding to its cytoplasmic receptor to form a glucocorticoid receptor complex that is then conveyed to the nucleus under the control of certain chaperones. 15 , 16 In the nucleus, the glucocorticoid receptor binds directly to glucocorticoid response elements in promoter regions 17 to regulate transcription, or controls the function of other transcription factors, such as NF- κ B and AP-1. 18 This affects the expression of several target genes, one of which is transforming growth factor- β (TGF β ).…”

Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1

“…GCs act by binding their cognate receptor, the GC receptor (GR), a member of the nuclear hormone receptor family. As a monomer, ligand-activated GR represses the activities of pro-inflammatory transcription factors, such as activator protein 1, nuclear factor kappa B (NF-κB) and interferon regulatory factor 3, by a tethering mechanism called transrepression 9 10 . On the other hand, the direct binding of dimerized GR to response elements in the DNA (GC-response elements) induces gene transcription, commonly referred to as transactivation.…”