Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids

Mol Endocrinol. 1995 Apr;9(4):401-12. doi: 10.1210/mend.9.4.7659084.


Glucocorticoids are efficient antiinflammatory agents, and their effects include transcriptional repression of several cytokines and adhesion molecules. Whereas glucocorticoids down-regulate the expression of genes relevant during inflammation, nuclear factor (NF)-kappa B/Rel proteins function as important positive regulators of these genes. The expression of intercellular adhesion molecule-1 (ICAM-1), which plays an essential role in recruitment and migration of leukocytes to sites of inflammation, is also down-regulated by glucocorticoids. We found that a functional NF-kappa B site in the ICAM-1 promoter, which can be activated by either 12-O-tetradecanoylphorbol-13-acetate or tumor necrosis factor-alpha (TNF alpha), is also the target for glucocorticoids. In this report we present evidence that the ligand-activated glucocorticoid receptor (GR) is able to repress RelA-mediated activation of the ICAM-1 NF-kappa B site. Conversely, transcriptional activation by GR via a glucocorticoid response element is specifically repressed by RelA, but not by other NF-kappa B/Rel family members. Mutational analysis of GR demonstrates that the DNA binding domain and the ligand binding domain are required for the functional repression of NF-kappa B activation. Despite the importance of the DNA binding domain, we found that the transcriptional repression of NF-kappa B, mediated by GR, is not caused by binding of GR to the ICAM-1 NF-kappa B element, but by a physical interaction between the GR and RelA protein. The repressive effect of GR on NF-kappa B-mediated activation was not shared by other steroid/thyroid receptors. Only the progesterone receptor, which belongs to the same subfamily as GR and which possesses high homology with GR, was able to repress NF-kappa B-mediated transcription. These studies highlight a possible molecular mechanism that can explain the antiinflammatory effects of glucocorticoid treatment during inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Base Sequence
  • Cell Line, Transformed
  • Cells, Cultured
  • Chlorocebus aethiops
  • Gene Expression Regulation / drug effects*
  • Glucocorticoids / pharmacology*
  • Humans
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • Promoter Regions, Genetic
  • Receptors, Glucocorticoid / drug effects
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / physiology*
  • Receptors, Steroid / metabolism
  • Recombinant Fusion Proteins / biosynthesis
  • Steroids
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor RelA
  • Transcriptional Activation / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology


  • Anti-Inflammatory Agents
  • Glucocorticoids
  • NF-kappa B
  • Receptors, Glucocorticoid
  • Receptors, Steroid
  • Recombinant Fusion Proteins
  • Steroids
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Tetradecanoylphorbol Acetate