Review
Non-genomic Effects of Glucocorticoids: An Updated View

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Highlights

GC genomic and non-genomic effects involve distinct mechanisms of action but play complementary roles in mediating the anti-inflammatory effects of GCs.

GCs are mostly used in asthma as a ‘controller’ therapy because of their delayed effects, but since GCs recently have been shown to ‘rapidly’ enhance the effects of bronchodilators, they could be used also as a ‘rescue’ therapy, especially in combination with β2 agonists.

Compelling evidence proposed the emerging role of (airway) structural cells as a major target for GC non-genomic effects that act through poorly understood, cell-specific mechanisms.

Both inflammatory pathways and non-inflammatory pathways such as calcium mobilization, muscle tone, and reactive oxygen species are targets for the GC non-genomic effects.

Designing a GC able to solely act through non-genomic pathways may prevent some of the GC side effects often engendered by GC genomic effects.

Glucocorticoid (GC) anti-inflammatory effects generally require a prolonged onset of action and involve genomic processes. Because of the rapidity of some of the GC effects, however, the concept that non-genomic actions may contribute to GC mechanisms of action has arisen. While the mechanisms have not been completely elucidated, the non-genomic effects may play a role in the management of inflammatory diseases. For instance, we recently reported that GCs ‘rapidly’ enhanced the effects of bronchodilators, agents used in the treatment of allergic asthma. In this review article, we discuss (i) the non-genomic effects of GCs on pathways relevant to the pathogenesis of inflammatory diseases and (ii) the putative role of the membrane GC receptor. Since GC side effects are often considered to be generated through its genomic actions, understanding GC non-genomic effects will help design GCs with a better therapeutic index.

Section snippets

Mechanism of Action of GCs

GCs primarily mediate their effects by activating the ubiquitously expressed intracellular GC receptor (GR; see Glossary) [1]. In its inactive state, the GR resides in the cytoplasm and, upon ligand activation, it translocates to the cell nucleus to interact with GC response elements, thereby producing genomic actions that alter protein expression. Interestingly, evidence suggests that GCs also manifest almost immediate non-genomic actions on several signaling processes [2]. GC non-genomic

GCs Exert Rapid Effects on Levels of Intracellular Calcium

Studies suggest that GC rapidly (within seconds) modulates basal intracellular calcium ([Ca2+]i) levels and agonist-induced calcium mobilization (Tables 2 and 3 ).

GCs Rapidly Modulate Skeletal and Smooth Muscle Function

Several studies have reported variable acute effects of GCs on muscle reactivity and tone. The specific example of airway smooth muscle (ASM) cells in the pathogenesis of inflammatory diseases is highlighted in Box 1. In mouse skeletal myotubes (C2C12 immortalized myoblasts), treatment with dexamethasone (for less than 20 min) reduced glucose uptake induced by electrical pulse stimulation-mediated contraction, in a Ca2+/calmodulin protein kinase II (CaMKII)- and AMP-activated protein kinase

GCs Exert Rapid Effects on Reactive Oxygen Species/Reactive Nitrogen Species

Studies demonstrated a rapid effect of GCs on reactive oxygen species (ROS) generation and the involvement of nitric oxide (NO) in mediating some GC effects. An example of the role NO/ROS in the pathogenesis of inflammatory disease is highlighted in Box 2. In breast cancer cells, cortisol rapidly increased levels of ROS and reactive nitrogen species (RNS) (as early as 15 min) and induced DNA damage. The GR antagonist RU486 blocked the cortisol effect, while Nω-nitro-l-arginine methyl ester

GCs Exert Acute Effects on Inflammatory and Apoptotic Pathways

Evidence shows rapid non-transcriptional actions of GCs on inflammation both in transformed cells and immune cells. In transformed cells, such as A549 adenocarcinoma cells, acute exposure (as early as 1 min) to dexamethasone rapidly inhibited epidermal growth factor (EGF)-induced arachidonic acid release, an important mediator of inflammation [36]. This inhibitory effect was due to hindering the recruitment of Grb2, p21ras, and Raf to the EGF receptor (EGFR) through a GR-dependent

Potential Role of a Putative mGR in Mediating the Rapid Effects of GCs

As described previously, the rapid non-genomic effects can, at least in part, be mediated through a putative mGR. Over the years, caveolin-1 (Cav-1), the major protein component of caveolae, has been implicated as a scaffold for the organization of several cytoplasmic signal complexes at the plasma membrane 54, 55. In lung epithelial cells (A549), dexamethasone treatment leads to a rapid (within 2 min) phosphorylation of Cav-1 and protein kinase B (PKB)/Akt in a Src-dependent manner [56].

Concluding Remarks and Future Perspectives

Although we have some insight into how GCs regulate different signaling pathways in a non-genomic manner, future in-depth investigations are warranted to further unravel details of these complex interactions. Indeed, key questions (see Outstanding Questions) still need careful consideration, and additional research must address several important issues: (i) the differential nature of non-genomic effects of GC in immune cells versus non-immune/structural cells; (ii) differences between

Acknowledgments

This work was funded by National Institutes of Health grants 7R01HL111541-07 (O.T.), HL 2P01HL114471-06 (R.A.P.), and GM107094 (R.O.).

Glossary

Calcium mobilization
intracellular process triggered by external stimuli (e.g., contractile agonists) where calcium is released to be engaged in different cellular functions such as increased muscle reactivity and contraction. Calcium is usually acquired from extracellular sources (calcium influx) or intracellular stores (e.g., endoplasmic reticulum).
Genomic action
action that modulates the expression of genes. It involves transcriptional processes where an activated transcriptional factor

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