title: Mineralocorticoid Receptor (MR) trans-Activation of Inflammatory AP-1 Signaling: DEPENDENCE ON DNA SEQUENCE, MR CONFORMATION, AND AP-1 FAMILY MEMBER EXPRESSION.
abstract: Glucocorticoids are commonly used to treat inflammatory disorders. The glucocorticoid receptor (GR) can tether to inflammatory transcription factor complexes, such as NFκB and AP-1, and trans-repress the transcription of cytokines, chemokines, and adhesion molecules. In contrast, aldosterone and the mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. Although MR has been shown to weakly repress NFκB, its role in modulating AP-1 has not been established. Here, the effects of GR and MR on NFκB and AP-1 signaling were directly compared using a variety of ligands, two different AP-1 consensus sequences, GR and MR DNA-binding domain mutants, and siRNA knockdown or overexpression of core AP-1 family members. Both GR and MR repressed an NFκB reporter without influencing p65 or p50 binding to DNA. Likewise, neither GR nor MR affected AP-1 binding, but repression or activation of AP-1 reporters occurred in a ligand-, AP-1 consensus sequence-, and AP-1 family member-specific manner. Notably, aldosterone interactions with both GR and MR demonstrated a potential to activate AP-1. DNA-binding domain mutations that eliminated the ability of GR and MR to cis-activate a hormone response element-driven reporter variably affected the strength and polarity of these responses. Importantly, MR modulation of NFκB and AP-1 signaling was consistent with a trans-mechanism, and AP-1 effects were confirmed for specific gene targets in primary human cells. Steroid nuclear receptor trans-effects on inflammatory signaling are context-dependent and influenced by nuclear receptor conformation, DNA sequence, and the expression of heterologous binding partners. Aldosterone activation of AP-1 may contribute to its proinflammatory effects in the vasculature.
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 doughertye@cc.nih.gov.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Dougherty
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Elinoff
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Ferreyra
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Angela
authors.initials: A
authors.lastname: Hou
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Rongman
authors.initials: R
authors.lastname: Cai
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Sun
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Blaine
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Shuibang
authors.initials: S
authors.lastname: Wang
authors.affiliation: From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892 rdanner@nih.gov.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000737:chemistry; D015870:Gene Expression; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D009154:Mutation; D016328:NF-kappa B / Q000276:immunology*; D000072417:Protein Domains; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D018161:Receptors, Mineralocorticoid / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000276:immunology*
chemical_list: D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D018808:Transcription Factor AP-1; D004247:DNA
keywords: AP1 transcription factor (AP-1); NF-κB transcription factor; glucocorticoid receptor; inflammation; mineralocorticoid receptor; nuclear receptor; trans-repression