Targeting glucocorticoid side effects: selective glucocorticoid receptor modulator or glucocorticoid-induced leucine zipper? A perspective.
Glucocorticoids (GCs) are steroid hormones that are necessary for life and important in health and disease. They regulate crucial homeostatic functions, including metabolism, cell growth, and development. Although GCs are regulated by circadian rhythm, increased production is associated with stress. Synthetic GCs are a valuable resource for anti-inflammatory and immunosuppressive therapy. Natural and synthetic GCs transduce signals mainly through GC receptor (GR) activation. Extensive research has explored the downstream targets of the GR, and optimization of GC therapy has required collaborative efforts. One highly promising approach involves new dissociative GR modulators. Because transrepression and transactivation of GR genes induce beneficial and adverse effects, respectively, this approach favors transrepression. Another approach involves the use of GC-dependent genes to generate proteins to mediate therapeutic GC effects. In a third approach, drug discovery is used to identify agents that selectively target GR isoforms to obtain differential gene transcription and effects. In this review, we focus on mechanisms of GR function compatible with the use of dissociative drugs. We highlight GC-induced leucine zipper (GILZ), a gene cloned in our laboratory, as a mediator of GC anti-inflammatory and immunosuppressive effects, to outline our perspective on the future of GC therapy.