Inhibition of Glucocorticoid-induced Apoptosis in 697 Pre-B Lymphocytes by the Mineralocorticoid Receptor N-terminal Domain

Planey, Sonia Lobo; Derfoul, Assia; Steplewski, Andrzej; Robertson, Noreen M.; Litwack, Gerald

doi:10.1074/jbc.m205085200

Cited by 40 publications

(38 citation statements)

References 66 publications

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“…This MR-mediated repression of GR activity has also been described in mammals and seems to be a typical outcome of GR and MR co-localization (Liu et al 1995, Derfoul et al 1998, Ou et al 2001, Planey et al 2002, although synergistic transcriptional activation between the GR and the MR was also described by Trapp et al (1994). Such observations of mutual inhibition of transcriptional activity have also been described with androgen and GRs, which is consistent with a high degree of sequence homology in the dimer interface of DBD between these nuclear receptors (Chen et al 1997).…”

Section: Discussionsupporting

confidence: 69%

“…Thus, study of the regulation of the human Na/K-ATPase beta1 subunit promoter in CV1 cells has shown that MR interaction with the GR on the promoter effectively down-regulates transcription, and this inhibition was mediated by the N-terminal domain of the MR (NTD-MR) (Derfoul et al 1998). More recently, the effect of the NTD-MR on glucocorticoid-induced apoptosis in the glucocorticoid-sensitive pre-B lymphoma cell line was analyzed, and results suggest that the NTD-MR mediates the inhibition of glucocorticoid-regulated gene transcription by glucocorticoids (GC) through heterodimerization with the GR (Planey et al 2002). In neuronal cells, there is also evidence that heterodimerization of the MR and the GR mediates direct corticosteroid-induced trans-repression of the 5-HT1A receptor promoter (Ou et al 2001).…”

Section: Figurementioning

confidence: 99%

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Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro

Kiilerich¹,

Triqueneaux²,

Christensen³

et al. 2015

Journal of Molecular Endocrinology

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The salmonid corticosteroid receptors (CRs), glucocorticoid receptors 1 and 2 (GR1 and GR2) and the mineralocorticoid receptor (MR) share a high degree of homology with regard to structure, ligand-and DNA response element-binding, and cellular co-localization. Typically, these nuclear hormone receptors homodimerize to confer transcriptional activation of target genes, but a few studies using mammalian receptors suggest some degree of heterodimerization. We observed that the trout MR confers a several fold lower transcriptional activity compared to the trout GRs. This made us question the functional relevance of the MR when this receptor is located in the same cells as the GRs and activated by cortisol. A series of co-transfection experiments using different glucocorticoid response elements (GREs) containing promoter-reporter constructs were carried out to investigate any possible interaction between the piscine CRs. Co-transfection of the GRs with the MR significantly reduced the total transcriptional activity even at low MR levels, suggesting interaction between these receptors. Co-transfection of GR1 or GR2 with the MR did not affect the subcellular localization of the GRs, and the MR-mediated inhibition seemed to be independent of specific activation or inhibition of the MR. Site-directed mutagenesis of the DNA-binding domain and dimerization interface of the MR showed that the inhibition was dependent on DNA binding but not necessarily on dimerization ability. Thus, we suggest that the interaction between MR and the GRs may regulate the cortisol response in cell types where the receptors co-localize and propose a dominant-negative role for the MR in cortisolmediated transcriptional activity.

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Section: Discussionsupporting

confidence: 69%

Section: Figurementioning

confidence: 99%

Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro

Kiilerich¹,

Triqueneaux²,

Christensen³

et al. 2015

Journal of Molecular Endocrinology

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“…19,31 However, a similar mechanism does not appear to operate in the case of autocrine regulation mediated by active GCs since total GR expression was constant throughout differentiation ( Figure 1C; our unpublished data). Furthermore, we have detected no evidence of increased expression of either GR␤ or the mineralocorticoid receptor (both of which may act as receptor "decoys" 22,42 ) in mature DCs. These findings suggest that other GR-independent factors such as postreceptor accessory pathways (eg, invoked by nuclear factor-B activation) contribute to GC resistance.…”

Section: Discussionmentioning

confidence: 85%

Expression of 11β-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells

Freeman

Hewison

Hughes

et al. 2005

Blood

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Glucocorticoids (GCs) exert powerful antiinflammatory effects that may relate in part to their ability to restrict the differentiation and function of dendritic cells (DCs). Although these inhibitory effects are dependent upon GCs binding to nuclear glucocorticoid receptors (GRs), fine-tuning of GR signaling is achieved by prereceptor interconversion of cortisol that binds GRs with high affinity and cortisone that does not. We show for the first time that human monocyte-derived DCs are able to generate cortisol as a consequence of up-regulated expression of the enzyme 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1). Immature DCs demonstrate selective enhancement of 11␤-HSD1 reductase activity, leading to increased conversion of inactive cortisone to active cortisol. Enhancement of GC bioavailability is maintained or increased upon terminal differentiation induced by signals associated with innate immune activation. In marked contrast, maturation induced by CD40 ligation leads to a sharp reduction in cortisol generation by DCs. The differentiation of DCs from monocyte precursors is inhibited at physiologic concentrations of inactive cortisone, an effect that requires activity of the 11␤-HSD1 enzyme. In conclusion, prereceptor regulation of endogenous GCs appears to be an important determinant of DC function and represents a potential target for therapeutic manipulation. ( IntroductionSynthetic derivatives of naturally occurring glucocorticoids (GCs) have major anti-inflammatory and immunosuppressive properties that make them suitable for the treatment of autoimmune disease or the prevention of allograft rejection. 1 Rational design of novel synthetic GC derivatives or of strategies that enable their optimal use requires an improved understanding of how exogenous and endogenous GCs exert their effects upon the immune system. Studies in vitro which use GCs at supraphysiologic concentrations suggest that major cellular targets are T cells 2,3 and dendritic cells (DCs). [4][5][6][7][8][9] In the latter case, GCs inhibit in vitro differentiation of DCs from their precursor cells [4][5][6]9 and impair their capacity to undergo terminal differentiation or generate proinflammatory cytokines. [5][6][7][8][9] The role of endogenous GCs in modulating DC development or function however is unknown.Crucial to any concept that seeks to explain how endogenous GCs influence DC development is an appreciation of how GC levels are regulated in vivo. Endogenous GCs exist either as active 11-hydroxy ligands (eg, cortisol) that bind glucocorticoid receptor ␣ (GR␣) or inactive 11-keto derivatives which do not (eg, cortisone). 10,11 Fine-tuning of active GC bioavailability in peripheral tissues is regulated by prereceptor interconversion of inactive and active ligands mediated by 2 isozymes of 11␤-hydroxysteroid dehydrogenase (11␤-HSD) that catalyze the so-called "cortisolcortisone" shuttle. 10,11 Inactivation of cortisol by dehydrogenation to cortisone is mediated by 11␤-HSD2. In the kidney, this activity prevents competition betwee...

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“…Glucocorticoid treatment caused repression of BCL2A1 mRNA expression in lymphoma and thymocyte cell lines [25,26]. In addition, direct fetal cortisol infusion and maternal betamethasone administration in sheep have been shown to reduce the number of binucleate cells [15,16].…”

Section: Discussionmentioning

confidence: 99%

Differences in Apoptotic Status in the Bovine Placentome between Spontaneous and Induced Parturition

Hirayama

Ushizawa

Takahashi

et al. 2012

Journal of Reproduction and Development

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Abstract.We conducted this study to analyze apoptotic changes in the bovine placentome at spontaneous and induced parturition. Cows delivered i) after the administration of dexamethasone followed by prostaglandin F 2α and estriol, ii) after the administration of prostaglandin F 2α and estriol or iii) spontaneously. Prepartum changes in plasma progesterone and estradiol-17β concentrations were similar between spontaneous and induced parturition. Messenger RNA of BCL2-related protein A1 (BCL2A1), an antiapoptotic gene, was expressed by trophoblast binucleate cells and caruncular epithelial cells. Quantitative RT-PCR showed that the expression of BCL2A1 mRNA in cotyledonary and caruncular portions was significantly lower in spontaneous parturition than induced parturition. The expression of BCL2-associated X protein (BAX) mRNA, a proapoptotic gene, was significantly higher in cotyledons at spontaneous parturition than parturition induced without dexamethasone. Caspase-3 (CASP3) mRNA and pre-activated CASP3 protein were predominantly detected in caruncular epithelial cells regardless of how parturition proceeded. Activated CASP3 protein was found in trophoblast uninucleate cells and binucleate cells rather than caruncular epithelial cells. In spontaneous parturition, intense staining of activated CASP3 was detected in caruncular epithelial cells. Spontaneous and dexamethasone-induced parturition increased apoptotic cells in the placentome compared with parturition induced without dexamethasone. The number of binucleate cells was significantly decreased in spontaneous parturition. The present results suggest that although the clinical dose of dexamethasone induces apoptosis in the placentome at term, neither dexamethasone nor prostaglandin F 2α evoke normal physiological changes in the placentome during delivery such as a change in the balance of apoptosis-related genes and disappearance of binucleate cells. A ppropriate regulation of cell proliferation and regression in the placentome is essential to maintain and complete gestation. In the bovine placentome, the number of apoptotic cells increases as pregnancy progresses and is significantly high at around parturition [1,2]. The facilitation of apoptosis seems to reflect placental maturity during the peripartum period. Recent studies have shown that the status of apoptosis in the placentome correlates with the incidence of a retained placenta after parturition [1,3]. In addition, artificial induction of parturition by the administration of a glucocorticoid and/ or prostaglandin (PG) F 2α also frequently results in a retained placenta [4,5]. These findings suggest that apoptosis in the placentome is required for detachment of the fetal membrane in the early postpartum period, but apoptotic status and its control in the placentome around parturition are not fully understood.Most cells undergoing apoptosis execute the death program by activating a hierarchy of caspases [6]. In the murine placenta, apoptotic cells and the expression of caspase-3 (CASP3), one of the key ...

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Inhibition of Glucocorticoid-induced Apoptosis in 697 Pre-B Lymphocytes by the Mineralocorticoid Receptor N-terminal Domain

Cited by 40 publications

References 66 publications

Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro

Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro

Expression of 11β-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells

Differences in Apoptotic Status in the Bovine Placentome between Spontaneous and Induced Parturition

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