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.
Kolla
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Department of Biochemistry and Molecular Pharmacology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Litwack
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D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016328:NF-kappa B / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D016328:NF-kappa B; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone