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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1646
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 6 3505-3509
Copyright © 2005 by The Endocrine Society

The Human Glucocorticoid Receptor (GR) Isoform ß Differentially Suppresses GR{alpha}-Induced Transactivation Stimulated by Synthetic Glucocorticoids

Oren Fruchter, Tomoshige Kino, Emmanouil Zoumakis, Salvatore Alesci, Massimo De Martino, George Chrousos and Ze’ev Hochberg

Pediatric and Reproductive Endocrinology Branch (O.F., T.K., E.Z., S.A., M.D.M., G.C., Z.H.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Meyer Children’s Hospital (O.F., Z.H.), Rambam Medical Center, Haifa 31096, Israel

Address all correspondence and requests for reprints to: Oren Fruchter, M.D., Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892. E-mail: o_fruchter{at}rambam.health.gov.il


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The ß-isoform of human glucocorticoid receptor ß (hGRß) acts as a natural dominant negative inhibitor of hGR{alpha}-induced transactivation of glucocorticoid-responsive genes. We determined hGRß ability to suppress hGR{alpha} transactivation that was induced by commonly used synthetic glucocorticoids. HepG2/C3A cells were transiently cotransfected with GR cDNA and a glucocorticoid-responsive promoter, luciferase (MMTV-luc). Transfected cells were incubated for 16 h with glucocorticoid and luciferase. For each compound, a dose-response curve was constructed, and half-maximal effective concentrations and maximal transcriptional activities were compared. hGRß, at a 1:1 ratio to hGR{alpha}, differentially suppressed hGR{alpha}-induced maximal transcriptional activity stimulated by triamcinolone, dexamethasone, hydrocortisone, and betamethasone (by 96, 68, 62, and 49%, respectively) but not by methylprednisolone. The suppressive effect of hGRß on hGR{alpha}-induced transactivation was stronger at lower concentrations of all tested glucocorticoids, whereas it was blunted at higher concentrations. We conclude that the potency of the dominant negative effect of hGRß on hGR{alpha}-induced transactivation depends on both the type and the dose of the synthetic glucocorticoids in use. These results may provide helpful information concerning the selection of synthetic glucocorticoids for treatment of pathological conditions in which hGRß modulates the sensitivity of tissues to glucocorticoids.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
GLUCOCORTICOIDS PLAY A pivotal role in maintaining internal homeostasis in response to external stimuli, having broad effects on numerous biochemical and cellular activities of many organs and tissues. At pharmacological doses, glucocorticoids demonstrate strong antiinflammatory and immunosuppressive effects. These effects place them among the most important therapeutic compounds for treatment of many autoimmune/allergic, inflammatory, and lymphoproliferative diseases, as well as potent suppressors of rejection reaction in organ transplantation (1, 2). Because glucocorticoids have major impact on the course of these diseases, many synthetic glucocorticoids had been synthesized to increase and prolong their biological glucocorticoid activity and to reduce their often undesirable mineralocorticoid potency.

The glucocorticoid receptor (GR), an intracellular receptor protein and a member of the steroid/thyroid/retinoic acid and orphan nuclear receptor superfamily, mediates the numerous biological effects of glucocorticoids (3, 4). The human (h) GR gene, located on chromosome 5, encodes the highly homologous receptor isoforms hGR{alpha} and -ß, with alternative splicing of exons 9{alpha} and -ß (5, 6, 7). These isoforms diverge beyond amino acid 727, with hGR{alpha} having 50 additional amino acids and hGRß having 15 additional nonhomologous amino acids in their C-terminal portion. hGR{alpha} is a classic receptor that binds glucocorticoids and mediates their known activities, whereas hGRß does not bind ligand and has a dominant negative effect on hGR{alpha}-induced transactivation. hGR{alpha} is ubiquitously expressed in almost all human tissues and cells (8) and, in the absence of ligand, resides in the cytoplasm as a heterocomplex with several heat shock proteins and their auxiliary molecules.

In contrast to the well-known activities of hGR{alpha}, the physiological role and action of hGRß are unclear. hGRß is also ubiquitously expressed in almost all tissues, usually at lower concentrations than hGR{alpha}, with the exception of epithelial cells and neutrophiles (7, 8, 9, 10, 11). Most (12, 13, 14), but not all (15, 16), transfection studies revealed that hGRß acts as a natural dominant negative inhibitor of hGR{alpha}-induced transactivation of glucocorticoid-responsive genes.

In the present study, we determined the ability of hGRß to suppress hGR{alpha} transactivation induced by several commonly used synthetic glucocorticoids. We found that each glucocorticoid has different susceptibility to the transdominant effect of hGRß.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Synthetic glucocorticoids (dexamethasone, hydrocortisone, methylprednisolone, prednisolone, betamethasone, and triamcinolone) were purchased from Sigma (St. Louis, MO). They were initially dissolved in ethanol at a concentration of 10–2 M and stored at –70 C until used.

Cell cultures

Human hepatocellular carcinoma cell, HepG2/C3A (17) (CRL-10741; American Type Cell Culture Collection, Manassas, VA) were maintained in DMEM:nutrient mixture F-12 (DMEM/F-12) containing 10% heat-inactivated fetal bovine serum (FBS), 100 U/ml penicillin, and 100 µg/ml streptomycin in 5% CO2 at 37 C.

Plasmids

We used the following plasmids.

1. pMMTV-Luc contains the luciferase gene under the control of the mouse mammary tumor virus (MMTV) promoter (donation of G. L. Hager, NIH, Bethesda, MD). MMTV promoter has four functional glucocorticoid-responsive elements.

2. pRShGR{alpha} and pRShGRß (gifts from R. M. Evans, Salk Institute, La Jolla, CA) contain the full-length coding region of hGR{alpha} and hGRß, respectively, under the control of the constitutively active Rous sarcoma virus promoter.

3. pSV40-ß-Gal (Promega, Piscataway, WI) encoding for ß-galactosidase was used as an internal control for transfection efficacy.

4. The plasmid pRSV-erbA–1 contains the thyroid receptor cDNA in inverse orientation, but is otherwise similar to pRShGR{alpha} and ß plasmids; pRSV-erbA–1 was used to yield a constant and equal amount of transfected DNA in all the experiments.

Transient transfection and reporter assay

Cells were plated in 100-mm plates 24 h before transfection in DMEM/F-12 containing 10% charcoal-stripped FBS (Hyclone Laboratories, Logan, UT) to obtain a confluence of 60–80% at the time of transfection. Two hours before transfection, medium was replaced by 12 ml Opti-MEM I (Life Technologies, Inc., Grand Island, NY). Cells were transfected with plasmids at indicated DNA concentrations using Lipofectamine 2000 (Invitrogen Corp., Carlsbad, CA) according to the manufacturer’s instructions. Six hours after transfection, medium was replaced by DMEM/F-12 containing 10% charcoal-stripped FBS, and cells were left to recover for an additional 12 h. Then, they were harvested and seeded onto a 96-well plate (Costar, Corning, NY) at a density of 2 x 104 cells/well. Thirty hours after transfection, the cells were incubated with the indicated synthetic glucocorticoids at concentrations ranging from 10–10 M to 10–6 M. After 16 h of incubation, the cells were lysed in 120 µl/well of passive lysis buffer (Promega), 50 µl of cell lysates were transferred to 96-well plates, and ß-galactosidase and luciferase activities were determined in a Wallac 1420 Victor (2) multilabel counter (Wallac Oy, Turku, Finland) using a Galacto-Light Plus (Tropix, Bedford, MA) or a Luciferase assay system (Promega), respectively.

Data analysis

Luciferase activity was normalized for ß-galactosidase activities to correct for transfection efficiency. Results in figures and tables represent the mean ± SEM obtained from three independent experiments that were individually performed in octaplicates. Statistical analysis of the data were performed using the Mann-Whitney U test or by nonparametric repeated measures ANOVA. Differences were regarded as significant when P < 0.05.


   Results
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 Abstract
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 Materials and Methods
 Results
Discussion
 References
 
We employed HepG2/C3A cells, which do not express functional hGR{alpha}. Glucocorticoid-related transcription from pMMTV-luc reporter was achieved only when pRShGR{alpha} was cotransfected with this reporter plasmid (data not shown). Treatment of cells transfected with both pRShGR{alpha} and pMMTV-luc with 10–7 M dexamethasone gave a 600-fold enhancement of luciferase activity, compared with cells unexposed to the steroid. In these cells, hGRß inhibited hGR{alpha}-induced transactivation in both a compound-dependent and dose-dependent manner (Fig. 1Go).



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  		FIG. 1. Maximal transactivation activity of synthetic glucocorticoids at 10–7 M, and the transdominant negative activity of hGRß. HepG2/C3A cells were transfected with pMMTV-luc, hGR{alpha}-expressing plasmid, and hGRß-expressing plasmid at hGR{alpha}/hGRß ratio of 1:0 (open bars), 1:1 (gray bars), and 1:10 (black bars). The empty vector pRSV-erbA–1 was used to yield a constant amount (24 µg) of transfected DNA. Data are plotted as relative luciferase activity. Data represent the mean (±SE) of three independent experiments performed in octaplicates. D, Dexamethasone; H, hydrocortisone; M, methylprednisolone; P, prednisolone; T, triamcinolone; B, betamethasone.

 
At a 1:10 ratio of transfected hGR{alpha}:hGRß-expressing plasmids, hGRß strongly suppressed by more than 90% the maximal transcriptional activities of hGR{alpha} after stimulation by each glucocorticoid. At a 1:1 ratio of hGR{alpha}:hGRß, hGRß suppressed hGR{alpha}-induced maximal transcriptional activity that was stimulated by dexamethasone, prednisolone, hydrocortisone, triamcinolone and betamethasone but not by methylprednisolone. Percentages of hGRß-induced suppression are shown in Table 1Go. These results indicate that the transdominant negative effect of hGRß depends on the type of glucocorticoid that is used to activate hGR{alpha} transactivation.


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  		TABLE 1. Suppressive effect of hGRß on hGR{alpha} maximal transactivation stimulated with six synthetic glucocorticoids at 10–7 M concentration

 
We next examined the suppressive effect of hGRß on hGR{alpha}-induced transactivation stimulated by increasing concentrations of these glucocorticoid compounds. Dose-response curves of luciferase activity obtained in cells transfected with 1:0 and 1:1 ratios of hGR{alpha}- and hGRß-expressing plasmids are shown in Fig. 2Go. All glucocorticoids exhibited a dose-dependent effect on hGR{alpha}-mediated transcriptional activity. Expression in the cells of hGRß suppressed all titration curves. Using these results, we calculated EC50 (the half-maximal effective concentration of a compound) and relative potencies, obtained by dividing the EC50 of hydrocortisone (1:0 ratio) by that of each compound (Table 2Go). The decrease in potency induced by expression of hGRß was most pronounced for triamcinolone and betamethasone, whereas less than a 10-fold difference was observed for dexamethasone, methylprednisolone, prednisolone, and hydrocortisone.



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  		FIG. 2. Dose-response curves of hGR{alpha} transcriptional activity stimulated by six glucocorticoid compounds in cells transfected with hGRß-expressing plasmids. HepG2/C3A cells were transfected with pMMTV-luc, hGR{alpha}-expressing plasmid together with or without hGRß-expressing plasmid. pRSV-erbA–1 was used to yield a constant amount of transfected DNA. Dose-response curves are plotted for the 1:0 (solid line) and 1:1 (dashed line) ratios of hGR{alpha}:hGRß. Data are plotted as relative luciferase activity of three independent experiments, each performed in octaplicates.

 

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  		TABLE 2. The relative transactivation potencies (EC50) of synthetic glucocorticoids at different hGR{alpha}/hGRß ratios

 
We then calculated the suppressive effect of hGRß obtained at each concentration of tested glucocorticoid by comparing activities obtained with hGRß expression at 1:1 ratio and those achieved without hGRß coexpression (Fig. 3Go). Methylprednisolone was insensitive to the suppressive effect at 10–10 M and less sensitive than the other steroids at all other concentrations. Similar tendency was also observed with hGR{alpha}:hGRß at 1:10 ratio (data not shown).



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  		FIG. 3. Dose-dependent suppressive effect of hGRß in a hGR{alpha}/hGRß 1:1 ratio on hGR{alpha}-mediated relative luciferase activity, stimulated by each of the six synthetic glucocorticoids. The suppressive effect of hGRß is calculated by dividing luciferase activity obtained in cells transfected with 1:1 ratio of hGR{alpha}-/hGRß-expressing plasmids by those obtained in cells transfected with 1:0 ratio of these plasmids. D, Dexamethasone; H, hydrocortisone; M, methylprednisolone; P, prednisolone; T, triamcinolone; B, betamethasone.

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We addressed the differences between various commonly used synthetic glucocorticoids in terms of their ability to exert hGR{alpha}-dependent transactivation in a human liver cell line, HepG2/C3A. For most of the compounds tested, expression of hGRß at a ratio to hGR{alpha} 1:1 resulted in a significant inhibitory effect. Our results are in agreement with previous reports (12, 13, 14), but introduce new insight in both physiological and clinical perspectives. Previous groups used 10-fold higher amounts of hGRß-expressing plasmids than hGR{alpha} and studied the inhibitory effect under stimulation with dexamethasone. We showed a transdominant effect of hGRß at 1:1 ratio to hGR{alpha}, which is closer to physiological conditions, and tested it in a human tissue (8). We also demonstrated that hGRß inhibited the transactivation of most but not all synthetic glucocorticoids, which are the cornerstone of many antiinflammatory and immunosuppressive treatment protocols.

The equivocal findings and theories on the physiological role of hGRß are summarized in Refs. 6 and 18). Several mechanisms are hypothesized for this hGRß activity, including competition for binding glucocorticoid response elements (GREs), formation of transcriptional inactive hGR{alpha}/hGRß heterodimer, and titration of coactivators through its intact activation function 1 domain (14). The dominant negative effect of hGRß may be responsible, in part, for the development of reduced sensitivity of tissues to glucocorticoids in several pathological conditions, such as steroid resistant asthma (19, 20, 21, 22, 23), rheumatoid arthritis (24, 25), systemic lupus erythematosus, Crohn’s disease, ulcerative colitis, and various other diseases in which synthetic glucocorticoids play a pivotal role in management (26, 27, 28, 29, 30, 31).

Two separate important pharmacodynamic parameters were evaluated for each compound: potency and efficacy (32, 33). The former is reflected by the maximal transcriptional activity of a compound and is determined by maximal interaction of activated receptors to the transcriptional machineries of target genes. This depends on receptor density and the coupling of maximal receptor occupancy to the ultimate response and is reflected by EC50; it is mainly determined by its affinity to the receptor and by the intrinsic properties of molecules that have the ability to transduce the glucocorticoid signal. On the other hand, the transcriptional efficacy is tissue-specific and is determined by drug-tissue interaction. It is a reflection of the contribution of properties of both the drug and its receptor and properties of the target tissue in terms of receptor density and the coupling of receptor occupancy to the ultimate response.

To note, transcriptional potencies in the current work differ considerably from the well-established known in vivo biological potencies of glucocorticoids (2). Our results were derived from experiments performed in cell-culture deprived from any pre- and postreceptor-modulating mechanisms such as the prereceptor modification of glucocorticoids by 11ß-hydroxysteroid dehydrogenase that was addressed by us in previous reports (34, 35). Although GR-ß coexpression at a ratio of 1:1 resulted in a similar absolute relative luciferase unit of, for instance, methylprednisolone and hydrocortisone, we feel that it is the magnitude of suppression that is a better measure of eventual biological activity.

We demonstrate that overexpression of hGRß suppressed these two pharmacodynamic parameters of all tested glucocorticoids. However, different synthetic glucocorticoids had different susceptibility to hGRß transdominant negative activity. Binding of various glucocorticoids to the ligand-binding pocket of hGR{alpha} may induce different conformational changes in the whole molecule of hGR{alpha} in addition to its ligand-binding domain. hGRß may thus interact differently with activated hGR{alpha}. Binding of hGRß to hGR{alpha} might further modify differently the conformation of hGR{alpha} that subsequently produces discrete affinity to GREs and/or coactivator molecules or transcriptional machineries.

Coexpression of hGRß with hGR{alpha} reduced the EC50 of the latter’s transactivation activity that was induced by all glucocorticoids tested, suggesting that hGRß reduced ligand-binding activity of hGR{alpha}. We demonstrate that the dominant negative activity of hGRß was differentially exerted, depending on the dose of all tested glucocorticoids. Lower concentrations of glucocorticoids were more susceptible to inhibition by hGRß than higher concentrations. With more hGR{alpha} molecules that are activated by higher concentrations of any glucocorticoid, additional hGR{alpha} may escape physical interaction or competition with hGRß for the GRE and for limited amounts of coactivator molecules or transcription factors (14). We found that methylprednisolone was less affected by hGRß transdominant negative effect, compared with other steroids, a finding that may affect clinical decision-making in selecting a therapeutic derivative. The ratio of expressed hGRß to hGR{alpha} is highest in leukocytes (36, 37), which play a role in autoimmune, inflammatory, and allergic diseases and prevention of graft rejection. During these conditions, patients frequently develop glucocorticoid resistance, in which hGRß is overexpressed, possibly exerting its dominant negative effect.

Obviously one has to take into account the well-known drawbacks of results obtained in vitro and interpret them cautiously before they are applied in clinical use.

With this in mind, our data suggest that methylprednisolone may be the glucocorticoid of choice in the treatment of such pathological states.


   Acknowledgments
 
We thank Drs. R. M. Evans and G. L. Hager for providing their plasmids and Mr. K. Zachman for his technical assistance.


   Footnotes
 
First Published Online March 8, 2005.

Abbreviations: FBS, Fetal bovine serum; GR, glucocorticoid receptor; GRE, glucocorticoid response element; h, human; MMTV, mouse mammary tumor virus.

Received August 18, 2004.

Accepted February 23, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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