Inhibition of mineralocorticoid-mediated transcription by NF-kappaB.

Nuclear factor-kappaB (NF-kappaB) is a ubiquitous transcription factor that regulates the expression of multiple inflammatory and immune response genes and plays a critical role in host defense and in chronic inflammatory diseases. The mineralocorticoid receptor (MR) belongs to the steroid/thyroid hormone receptor super-family of ligand-induced transcription factors. We demonstrate a dose-dependent, mutual transcriptional antagonism between NF-kappaB and MR in transient transfection experiments. We also show that the antagonism is limited to the p65 subunit of NF-kappaB heterodimer but not p50. Transient cotransfection experiments with MR deletion constructs reveal the necessity of various N-terminal MR domains for this phenomenon. Inhibition of NF-kappaB by IkappaB relieves the repression of NF-kappaB function by MR. These data suggest that the p65 subunit of NF-kappaB interacts with MR indirectly and transrepresses MR activation.