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-Ake Gustafsson, Paul T. Van Der Saag

Research output: Contribution to journalArticle

453 Scopus citations

Abstract

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
Volume9
Issue number4
DOIs
StatePublished - Jan 1 1995

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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