Glucocorticoid repression of inflammatory gene expression shows differential responsiveness by transactivation- and transrepression-dependent mechanisms

PLoS One. 2013;8(1):e53936. doi: 10.1371/journal.pone.0053936. Epub 2013 Jan 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line, Tumor
  • Cycloheximide / pharmacology
  • Cytokines / genetics*
  • Dexamethasone / pharmacology*
  • Gene Expression / drug effects*
  • Gene Expression Profiling
  • Glucocorticoids / pharmacology
  • Humans
  • Inflammation Mediators / metabolism*
  • Interleukin-1beta / pharmacology
  • Linear Models
  • NF-kappa B / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Protein Synthesis Inhibitors / pharmacology
  • RNA Interference
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transcriptional Activation / drug effects*


  • Cytokines
  • Glucocorticoids
  • Inflammation Mediators
  • Interleukin-1beta
  • NF-kappa B
  • NR3C1 protein, human
  • Protein Synthesis Inhibitors
  • Receptors, Glucocorticoid
  • Dexamethasone
  • Cycloheximide