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

Eric Caldenhoven, Johan Liden, Sacha Wissink, Anja Van De Stolpe, Jan Raaijmakers, Leo Koenderman, Sam Okret, Jan Åke Gustafsson, Paul T. Van Der Saag

Research output: Contribution to journalArticlepeer-review

478 Scopus citations


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)-κB/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-κB site in the ICAM-1 promoter, which can be activated by either 12-O- tetradecanoylphorbol-13-acetate or tumor necrosis factor-α (TNFα), 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-κB site. Conversely, transcriptional activation by GR via a glucocorticoid response element is specifically repressed by RelA, but not by other NF-κB/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-κB activation. Despite the importance of the DNA binding domain, we found that the transcriptional repression of NF-κB, mediated by GR, is not caused by binding of GR to the ICAM-1 NF-κB element, but by a physical interaction between the GR and RelA protein. The repressive effect of GR on NF-κB- 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-κB-mediated transcription. These studies highlight a possible molecular mechanism that can explain the antiinflammatory effects of glucocorticoid treatment during inflammation.

Original languageEnglish (US)
Pages (from-to)401-412
Number of pages12
JournalMolecular Endocrinology
Issue number4
StatePublished - Apr 1995

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology


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