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

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.