Glucocorticoid receptors: finding the middle ground

Abstract

Glucocorticoids (GCs; referred to clinically as corticosteroids) are steroid hormones with potent anti-inflammatory and immune modulatory profiles. Depending on the context, these hormones can also mediate pro-inflammatory activities, thereby serving as primers of the immune system. Their target receptor, the GC receptor (GR), is a multi-tasking transcription factor, changing its role and function depending on cellular and organismal needs. To get a clearer idea of how to improve the safety profile of GCs, recent studies have investigated the complex mechanisms underlying GR functions. One of the key findings includes both pro- and anti-inflammatory roles of GR, and a future challenge will be to understand how such paradoxical findings can be reconciled and how GR ultimately shifts the balance to a net anti-inflammatory profile. As such, there is consensus that GR deserves a second life as a drug target, with either refined classic GCs or a novel generation of nonsteroidal GR-targeting molecules, to meet the increasing clinical needs of today to treat inflammation and cancer.

Figure 1. Graphic presentation of GC-associated side effects.

GCs can lead to a number of burdening side effects, depicted here, typically when used at higher doses and for a longer period of time, as is done with chronic inflammatory diseases.

Figure 2. GCs act at multiple levels in the inflammatory pathway.

An inflamed cell is depicted, along with inflammatory mediators (red), which show a signal transduction pathway leading to the activation of NF-κB and AP-1, which subsequently drive proinflammatory gene expression. GC-mediated and GR-triggered responses are depicted (green), including feedback and feedforward mediators, as described in the text. This includes upregulation and activities of various proteins, e.g., MKP-1, ZFP36, IRAK-M, and SphK1. IKK, IκBα kinase; IRAK, IL-1R–associated kinase-4; S1P, sphingosine-1-phosphate.

Figure 3. Influencing the effects of GCs.

(A) Factors that may contribute to the ability of GCs to shift the balance toward a net pro-inflammatory or antiinflammatory cellular state. An incoherent control system that includes a proinflammatory role for GCs is essential to prevent excessive inflammation and to effectively return to homeostasis. This results in a continuous competition between feedback and feedforward control. (B) The timing of treatment may contribute to the ability of GCs to shift the balance toward a net proinflammatory or antiinflammatory cellular state. This insight is important for critically (re-)evaluating in vitro and/or in vivo studies in which GCs are combined with an inflammatory trigger, here exemplified by LPS, in a laboratory-controlled environment. The order of addition and different durations of stimuli may result in marked differences in, and ongoing competition between, the predominant gene expression signature such as antiinflammatory (green-filled square), proinflammatory (red-filled square), or mixed (red/green-filled square). The expected outcome gene signatures represent the measurement point, where cells are collected and mRNA levels of relevant GC target genes, with pro- and antiinflammatory roles, are determined. The priming effect becomes of particular relevance under circumstances of increased stress prior to the inflammatory insult. Only one example is given here, but many variations in timing are possible.