Abstract
Binding of glucocorticoid to the glucocorticoid receptor (GR/NR3C1) may repress inflammatory gene transcription via direct, protein synthesis-independent processes (transrepression), or by activating transcription (transactivation) of multiple anti-inflammatory/repressive factors. Using human pulmonary A549 cells, we showed that 34 out of 39 IL-1β-inducible mRNAs were repressed to varying degrees by the synthetic glucocorticoid, dexamethasone. Whilst these repressive effects were GR-dependent, they did not correlate with either the magnitude of IL-1β-inducibility or the NF-κB-dependence of the inflammatory genes. This suggests that induction by IL-1β and repression by dexamethasone are independent events. Roles for transactivation were investigated using the protein synthesis inhibitor, cycloheximide. However, cycloheximide reduced the IL-1β-dependent expression of 13 mRNAs, which, along with the 5 not showing repression by dexamethasone, were not analysed further. Of the remaining 21 inflammatory mRNAs, cycloheximide significantly attenuated the dexamethasone-dependent repression of 11 mRNAs that also showed a marked time-dependence to their repression. Such effects are consistent with repression occurring via the de novo synthesis of a new product, or products, which subsequently cause repression (i.e., repression via a transactivation mechanism). Conversely, 10 mRNAs showed completely cycloheximide-independent, and time-independent, repression by dexamethasone. This is consistent with direct GR transrepression. Importantly, the inflammatory mRNAs showing attenuated repression by dexamethasone in the presence of cycloheximide also showed a significantly greater extent of repression and a higher potency to dexamethasone compared to those mRNAs showing cycloheximide-independent repression. This suggests that the repression of inflammatory mRNAs by GR transactivation-dependent mechanisms accounts for the greatest levels of repression and the most potent repression by dexamethasone. In conclusion, our data indicate roles for both transrepression and transactivation in the glucocorticoid-dependent repression of inflammatory gene expression. However, transactivation appears to account for the more potent and efficacious mechanism of repression by glucocorticoids on these IL-1β-induced genes.
Highlights
Glucocorticoids acting on the glucocorticoid receptor (GR/ NR3C1) are the most effective anti-inflammatory drugs available for multiple inflammatory conditions [1]
While other repressive mechanisms include GR binding to negative glucocorticoid response elements (GREs) in genes such as prolactin or proopiomelanocortin (POMC) [18,19], a lack of readily definable nGRE sites in the promoters of inflammatory genes argued against this mechanism of repression [5]
Direct nGRE-dependent repression of POMC is probably described by tethering type interactions of GR at the promoter sites required for transcriptional activation [20]
Summary
Glucocorticoids acting on the glucocorticoid receptor (GR/ NR3C1) are the most effective anti-inflammatory drugs available for multiple inflammatory conditions [1]. While the classical paradigm of action for nuclear hormone receptors, such as GR, is to activate gene transcription from hormone response elements, e.g. palindromic glucocorticoid response elements (GREs), this has not generally been thought to explain repression of inflammatory gene expression [1,4]. Rather this is attributed to multiple mechanisms of which transrepression, the ability of GR to directly repress gene transcription, is prominent [5]. While the degree to which these mechanisms apply in different systems remains to be fully investigated, it is essential to note that they cannot account for the well established, but widespread, post-transcriptional and translational repression that is elicited by glucocorticoids on inflammatory gene expression [3,6,25]
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