Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism.
Nuclear factor kappa B (NF-kappa B) is an inducible transcription factor that positively regulates the expression of proimmune and proinflammatory genes, while glucocorticoids are potent suppressors of immune and inflammatory responses. NF-kappa B and the glucocorticoid receptor (GR) physically interact, resulting in repression of NF-kappa B transactivation. In transient cotransfection experiments, we demonstrate a dose-dependent, mutual antagonism between NF-kappa B and GR. Functional dissection of the NF-kappa B p50 and p65 subunits and deletion mutants of GR indicate that the GR antagonism is specific to the p65 subunit of NF-kappa B heterodimer, whereas multiple domains of GR are essential to repress p65-mediated transactivation. Despite its repression of GR transactivation, p65 failed to block the transrepressive GR homologous down-regulation function. We also demonstrate that negative interactions between p65 and GR are not selective for GR, but also occur between NF-kappa B and androgen, progesterone B, and estrogen receptors. However, although each of these members of the steroid hormone receptor family is repressed by NF-kappa B, only GR effectively inhibits p65 transactivation. Further, in cotransfections using a chimeric estrogen-GR, the presence of the GR DNA-binding domain is insufficient to confer mutual antagonism to the p65-estrogen receptor interaction. Selectivity of p65 repression for each steroid receptor is demonstrated by I kappa B rescue from NF-kappa B-mediated inhibition. Together these data suggest that NF-kappa B p65 physically interacts with multiple steroid hormone receptors, and this interaction is sufficient to transrepress each steroid receptor. Further, the NF-kappa B status of a cell has the potential to significantly alter multiple steroid signaling pathways within that cell.
McKay
L I
LI
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Cidlowski
J A
JA
D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000502:physiology; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051996:Transcription Factor RelA; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha