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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 4113-4118
Copyright © 2004 by The Endocrine Society

Nur-Related Factor 1 and Nerve Growth Factor-Induced Clone B in Human Adrenal Cortex and Its Disorders

Liangying Lu, Takashi Suzuki, Yosuke Yoshikawa, Osamu Murakami, Yasuhiro Miki, Takuya Moriya, Mary H. Bassett, William E. Rainey, Yutaka Hayashi and Hironobu Sasano

Departments of Pathology (L.L., T.S., Y.Y., Y.M., T.M., H.S.), Pediatric Surgery (L.L., Y.H.), and Second Department of Internal Medicine (O.M.), Tohoku University School of Medicine, 980-8575 Sendai, Japan; and Division of Reproductive Endocrinology (M.H.B., W.E.R.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9032

Address all correspondence and requests for reprints to: Dr. Takashi Suzuki, Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail: t-suzuki{at}patholo2.med.tohoku.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Nerve growth factor-induced clone B (NGFI-B; NR4A1) and Nur-related factor 1 (Nurr1; NR4A2) are members of NGFI-B family of orphan receptors. We recently demonstrated induction of CYP11B2 (aldosterone synthase) by Nurr1 and NGFI-B, suggesting possible important roles of these transcriptional factors in the regulation of adrenocortical steroidogenesis. Therefore, we immunolocalized Nurr1 and NGFI-B in various human adrenal specimens to study their biological significance. In nonpathological adrenal glands (n = 25), Nurr1 and NGFI-B immunoreactivities were detected at high levels in the fetal definitive zone or postnatal zona glomerulosa. NGFI-B immunoreactivity was increased according to development in the zona fasciculata, reaching a level similar to that in the zona glomerulosa in adult adrenal cortex. In adrenocortical neoplasms (n = 44), Nurr1 immunoreactivity was higher in aldosteronoma than in Cushing’s adenoma or adrenocortical carcinoma. NGFI-B immunoreactivity was also higher in aldosteronoma than in adrenocortical carcinoma, but was not significantly different among the types of adenoma. Both Nurr1 and NGFI-B mRNA expressions were correlated with their immunoreactivities in adrenocortical neoplasms (n = 23), and mRNA expression of Nurr1 was significantly (P < 0.0001) associated with that of CYP11B2. These results suggest that the expression of Nurr1 and NGFI-B plays an important role in human adrenal cortex and its neoplasms, including possible regulation of steroidogenesis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
HUMAN ADRENAL CORTEX is composed of three distinct zones, i.e. the zonae glomerulosa, fasciculata, and reticularis. These three zones produce distinct steroid hormones, such as aldosterone in the zona glomerulosa, cortisol in the zona fasciculata, and dehydroepiandrosterone and dehydroepiandrosterone sulfate in the zona reticularis (1). This functional zonation results from the zone-specific expression of steroidogenic enzymes (2). It is also well known that adrenocortical neoplasms excessively produce various corticosteroids and are generally associated with an abnormal expression of steroidogenic enzymes (3, 4, 5). Therefore, it is very important to examine the possible regulation of adrenocortical steroidogenesis to obtain a better understanding of functions of the human adrenal cortex and its disorders.

Nerve growth factor-induced clone B (NGFI-B; NR4A1) and Nurr1 (Nur-related factor 1; NR4A2) belong to a NGFI-B family of nuclear hormone receptors as well as neuron-derived orphan receptor 1 (NR4A3) (6). These nuclear receptors activate transcription by binding to the NGFI-B-responsive elements (NBREs) located in the promoter region of target genes (7, 8) and regulate various cellular functions, such as the differentiation of neural cells (9, 10), the apoptosis of T lymphocytes in the thymus (11), and the modulation of retinoic acid signal transduction (12). The expression of Nurr1 and NGFI-B has been previously detected in murine adrenal glands (13). Very recently, we demonstrated that the human CYP11B2 (aldosterone synthase) gene, which is a key enzyme of aldosterone production, contains NBRE in the promoter region, and its expression was markedly induced by Nurr1 or NGFI-B (14). These in vitro data suggest important roles for Nurr1 and NGFI-B in the human adrenal cortex, including the regulation of steroidogenesis. However, a detailed examination of the expression of these nuclear receptors has not been reported in the human adrenal gland and its disorders. Therefore, after the previous in vitro study (14), we immunolocalized Nurr1 and NGFI-B in nonpathological and pathological specimens of human adrenal cortex. In addition, we examined mRNA expression of Nurr1 and NGFI-B in adrenocortical neoplasms using real-time RT-PCR and examined the correlation with CYP11B2 mRNA expression.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Human adrenal specimens

Sixty-nine human adrenal specimens were examined in this study. Twenty-five specimens of nonpathological adrenal glands were obtained from autopsy files (11–36 wk gestation and 1 d to 68 yr of age) from Tohoku University Hospital (Sendai, Japan). Forty-four cases of adrenocortical tumors (14 aldosteromas, 10 Cushing’s adenomas, 10 nonfunctioning adenomas with no clinical hormonal abnormalities, and 10 adrenocortical carcinomas) were retrieved from the surgical pathology files of Tohoku University Hospital. Adrenocortical carcinomas were histologically diagnosed based on the criteria of Weiss (15). These specimens were fixed in 10% formalin for 24–48 h at room temperature and embedded in paraffin wax.

Twenty-three cases of adrenocortical neoplasms were also available for real-time RT-PCR analysis (eight aldosteronomas, six Cushing’s adenomas, six nonfunctioning adenomas, and three adrenocortical carcinomas). Specimens for RNA isolation were snap-frozen and stored at –80 C.

Research protocols for this study were approved by the ethics committee at Tohoku University School of Medicine.

Immunohistochemistry

Rabbit polyclonal antibodies for Nurr1 (sc-991) and NGFI-B (1600045) were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA), and Geneka Biotechnology (Montréal, Canada), respectively. Utilization of these antibodies for immunohistochemistry has been reported previously (14).

Immunohistochemical analysis was performed employing the streptavidin-biotin amplification method using a Histofine Kit (Nichirei, Tokyo, Japan). Antigen retrieval was performed by heating the slides in an autoclave at 120 C for 5 min in citric acid buffer (2 mM citric acid and 9 mM trisodium citrate dehydrate, pH 6.0). The dilutions of the primary antibodies used in this study were: Nurr1, 1:250; and NGFI-B, 1:200. The antigen-antibody complex was visualized with 3,3'-diaminobenzidine solution [1 mM 3,3'-diaminobenzidine, 50 mM Tris-HCl buffer (pH 7.6), and 0.006% H2O2] and counterstained with hematoxylin. Immunohistochemical preabsorption tests for Nurr1 and NGFI-B were performed for negative controls of immunohistochemistry. Normal rabbit IgG was also used in place of the primary antibodies as a negative control.

Evaluation of immunoreactivity

After completely reviewing immunohistochemical sections, relative immunoreactivity for Nurr1 and NGFI-B in each zone of adrenocortex was evaluated by an H scoring system, as described by McCarty et al. (16) with some modifications (17). Briefly, adrenocortical cells were counted in each zone, and H-scores were subsequently generated by adding together 2 x the percentage of strongly stained nuclei, 1 x the percentage of weakly stained nuclei, and 0 x the percentage of negative nuclei, giving a possible range of 0–200. The H scores were independently and blindly evaluated by three of the authors (T.S., T.M., and H.S.) to obtain immunohistochemical data objectively, and the mean of the three values was used for analysis. The adrenals were classified into the following age groups in this study: 11–36wk gestation (n = 5), 1 d to 5 months of age (n = 4), 11 months to 8 yr of age (n = 5), 10–18 yr of age (n = 5), and 27–68 yr of age (n = 6). The relative immunoreactivity of tumor cells was also evaluated by H-scoring system described above. Statistical significance was evaluated using a Bonferroni test, and P < 0.05 was considered significant.

Real-time RT-PCR

Total RNA was carefully extracted from 23 specimens of adrenocortical neoplasms with guanidinium thiocyanate, followed by ultracentrifugation in cesium chloride. An RT kit (SuperScript II Preamplification System, Invitrogen Life Technologies, Inc., Grand Island, NY) was used in the synthesis of cDNA.

The Light Cycler System (Roche, Mannheim, Germany) was used to semiquantify the mRNA levels of Nurr1, NGFI-B, and CYP11B2 in 22 adrenocortical neoplasms by real-time PCR (18). Settings for the PCR thermal profile were: initial denaturation at 95 C for 1 min, followed by 40 amplification cycles of 95 C for 0 sec, annealing at 66 C (Nurr1, NGFI-B, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) or 60 C (CYP11B2) for 15 sec, and elongation at 72 C for 15 sec. The primer sequences used in this study are as follows: Nurr1: forward, 5'-AACCCTGACTATCAAATGAGTG-3'; reverse, 5'-CAATGCAGGAGAAGGCAGAAAT-3' (19); NGFI-B, forward, 5'-TCTGCTCAGGCCTGGTGCTAC-3'; reverse, 5'-GGCACCAAGTCCTCCAGCTTG-3' (20); CYP11B2: forward, 5'-TCCTGCTCTTCTTGCATCTGG-3'; reverse, 5'-TTTGCCCTGCAAATGGTTG-3' (21); and GAPDH: forward, 5'-TGAACGGGAAGCTCACTGG-3'; and reverse, 5'-TCCACCACCCTGTTGCTGTA-3' (22). To verify amplification of the correct sequences, PCR products were purified and subjected to direct sequencing. Nonpathological adrenal tissues were used as positive controls for Nurr1, NGFI-B, and CYP11B2. Negative control experiments lacked cDNA substrate to check for the possibility of exogenous contaminant DNA, and no amplified products were detected under these conditions. The mRNA level for Nurr1, NGFI-B, and CYP11B2 in each case has been summarized as a ratio of GAPDH, and subsequently evaluated as a ratio (percentage) compared with that in the positive controls (nonpathological adrenal glands = 100%).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Nonpathological adrenal cortex

Results for Nurr1 immunoreactivity in nonpathological human adrenocortex are summarized in Table 1AGo. Nurr1 immunoreactivity was detected in the nuclei of cortical cells, and its relative immunoreactivity was significantly (P < 0.0001) higher in the definitive zone (151 ± 19.8) than in the fetal zone (26.0 ± 4.74) of the fetal adrenal (Fig. 1AGo). At 11 months to 8 yr of age, immunoreactivity for Nurr1 was significantly higher in the zona glomerulosa (132 ± 8.95) than in the zonae fasciculata (58.8 ± 16. 5) and reticularis (15.3 ± 7.76; P < 0.0001, respectively). Nurr1 immunoreactivity in each zone was not significantly changed among the age groups examined (11 months to 8 yr, 10–18 yr, and 24–62 yr; Fig. 1Go, B and C).


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  		TABLE 1A. Relative immunoreactivity of Nurr1 in nonpathological human adrenal cortex

 


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  		FIG. 1. Immunohistochemistry for Nurr1 (A–D) and NGFI-B (E–H) in the adrenal cortex. A, Immunoreactivity for Nurr1 was detected at a high level in the nuclei of cortical cells in the definitive zone (D; 11 wk gestation). Fe, Fetal zone. B and C, Nurr1 immunoreactivity was detected at a high level in the zona glomerulosa (G; B, 5 yr of age; C, 49 yr of age). F, Zona fasciculata. D, Immunohistochemical preabsorption test for Nurr1 showed no specific immunoreactivity. E, NGFI-B immunoreactivity was detected at a high level in the definitive zone (14 wk gestation). F, At 11 months of age, immunoreactivity for NGFI-B was high in the zona glomerulosa, but low in the zona fasciculata. G, NGFI-B immunoreactivity was high in both zonae glomerulosa and fasciculata in the adrenocortex at 28 yr of age. H, Immunohistochemical preabsorption test for NGFI-B. No specific immunoreactivity was detected. Bar, 50 µm.

 
Results for NGFI-B immunoreactivity in nonpathological adrenal cortex are summarized in Table 1BGo. NGFI-B immunoreactivity was detected in the nuclei of cortical cells, and its relative immunoreactivity was significantly (P < 0.0001) higher in the definitive zone (122 ± 12.6) than in the fetal zone (24.2 ± 3.61; Fig. 1EGo). At 11 months to 8 yr of age, NGFI-B immunoreactivity was significantly higher in the zona glomerulosa (143 ± 12.5) than in the zonae fasciculata (53.0 ± 16.7) and reticularis (16.7 ± 5.54; P < 0.0001, respectively; Fig. 1FGo). Immunoreactivity for NGFI-B in the zona fasciculata was significantly increased in adolescent and adult age groups (10–18 yr, 113 ± 8.09; 27–68 yr, 132 ± 7.94) compared with that the 11 months to 8 yr of age group (P < 0.05, and P < 0.01, respectively; Fig. 1GGo), whereas NGFI-B immunoreactivity in the zonae glomerulosa and reticularis was not significantly changed.


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  		TABLE 1B. Relative immunoreactivity of NGFI-B in nonpathological human adrenal cortex

 
Adrenocortical tumor

The results for Nurr1 and NGFI-B immunoreactivity in adrenocortical tumors are summarized in Table 2AGo. Nurr1 relative immunoreactivity was significantly higher in aldosteronoma (121 ± 9.91; Fig. 2AGo) than in Cushing’s adenoma (62.1 ± 12.2; Fig. 2BGo) and adrenocortical carcinoma (60.0 ± 19.0; P < 0.001, respectively). NGFI-B immunoreactivity was also higher (P < 0.05) in aldosteronoma (122 ± 14.3; Fig. 2CGo) than in adrenocortical carcinoma (76.4 ± 13.6), but its difference among the types of adrenocortical adenoma did not reach statistical significance (Fig. 2DGo).


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  		TABLE 2A. Relative immunoreactivity of Nurr1 and NGFI-B in adrenocortical tumors

 


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  		FIG. 2. Immunohistochemistry for Nurr1 and NGFI-B in adrenocortical adenoma (A–D) and its attached nonneoplastic adrenal cortex (E–H). A–D, Nurr1 immunoreactivity was detected at a high level in the nuclei of tumor cells in aldosteronoma (A), whereas a great majority of tumor cells were negative for Nurr1 in Cushing’s adenoma (B). NGFI-B immunoreactivity was detected at a high level in aldosteronoma (C; same case as in A) or Cushing’s adenoma (D; same case as in B). E–H, Nurr1 (E and F) and NGFI-B (G and H) immunoreactivities were not significantly different in the attached nonneoplastic adrenocortex regardless of the type of adenoma. E–H were taken from the same slide as A–D, respectively. Bar, 50 µm.

 
The results for Nurr1 and NGFI-B immunoreactivity in attached nonneoplastic adrenal cortex of adenoma are summarized in Table 2Go, B and CGo. The relative immunoreactivity of Nurr1 and NGFI-B in attached nonneoplastic adrenocortex of adenoma was not significantly changed regardless of the type of adenoma examined (Fig. 2Go, E–H).


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  		TABLE 2B. Relative immunoreactivity of Nurr1 in the adjacent nonneoplastic adrenal cortex of adenomas

 

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  		TABLE 2C. Relative immunoreactivity of NGFI-B in the attached nonneoplastic adrenal cortex of adenomas

 
mRNA expression of Nurr1, NGFI-B, and CYP11B2 in adrenocortical adenoma

mRNA expression for Nurr1, NGFI-B, and CYP11B2 was detected as a specific single band (352, 358, and 121 bp, respectively) and was semiquantified by real-time RT-PCR. mRNA expression of Nurr1 and NGFI-B was detected in all adrenocortical adenomas examined, and the range of mRNA levels was 0.160–354% for Nurr1 and 12.0–223% for NGFI-B (nonpathological adrenal glands = 100%, respectively). As shown in Fig, 3, A and B, the mRNA levels of Nurr1 and NGFI-B were significantly correlated with the relative immunoreactivity (for Nurr1: r = 0.896; P < 0.0001; for NGFI-B: r = 0.787; P < 0.0001). mRNA expression of Nurr1 was significantly associated with that of CYP11B2 (r = 0.765; P < 0.0001; Fig. 3CGo), whereas no significant association was detected between NGFI-B and CYP11B2 mRNA levels (r = 0.213; P = 0.3301; Fig. 3DGo).



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  		FIG. 3. A and B, Association between the mRNA level and the relative immunoreactivity of Nurr1 (A) or NGFI-B (B) in 23 cases of adrenocortical adenomas. Significant positive associations were detected (for Nurr1: r = 0.896; P < 0.0001; for NGFI-B: r = 0.787; P < 0.0001). C and D, Association between the mRNA level of Nurr1 (C) or NGFI-B (D) and that of CYP11B2 in 23 adrenocortical adenomas. CYP11B2 mRNA was significantly correlated with Nurr1 mRNA (r = 0.765; P < 0.0001), but not with NGFI-B mRNA (r = 0.213; P = 0.3301).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Aldosterone is produced in the zona glomerulosa of the adrenal cortex through an interaction of several steroidogenic enzymes, including P450 side-chain cleavage (CYP11A), 3ß-hydroxysteroid dehydrogenase type 2 (3ßHSD2), CYP21, and CYP11B2. Among these enzymes, CYP11B2 is a specific enzyme for aldosterone biosynthesis, and it is expressed exclusively in the zona glomerulosa (23). Very recently, Bassett et al. (14) demonstrated that the CYP11B2 gene has two functional NBREs in the promoter region and was markedly up-regulated by Nurr1 and NGFI-B. In this study Nurr1 immunoreactivity was present at a high level in the zona glomerulosa or aldosteronoma, and mRNA expression of Nurr1 was significantly correlated with that of CYP11B2 in adrenocortical neoplasms. Therefore, it is suggested that Nurr1 expression plays an important role in aldosterone production through the induction of CYP11B2 in the zona glomerulosa of adrenal cortex or aldosteronoma. However, it is also true that Nurr1 immunoreactivity was detected at low levels in the zona fasciculata or adrenocortical neoplasms in addition to aldosteronoma in this study. Activation of Nurr1 depends on two so-called activation functions (AF1 and AF2), located at the N- or C-terminal regions, and it was partly regulated by the phosphorylation (24). Therefore, posttranslational modifications of Nurr1 are also considered to play some role in the zone-specific expression of CYP11B2 in the adrenal gland. In adrenocortical adenomas expressed Nurr1 mRNA at low levels, relative immunoreactivity of Nurr1 was variably detected (Fig. 3AGo). In these cases, evaluation of Nurr1 mRNA in tumor tissues may be reflected by heterogeneous expression of Nurr1 in neoplastic cells and/or amounts of stroma within the samples.

NGFI-B immunoreactivity was detected at high levels in the zonae glomerulosa and fasciculata in the nonpathological adrenal gland and in various types of adrenocortical adenoma. The zona fasciculata is mainly involved in cortisol production, and CYP11A, 3ßHSD2, CYP17, CYP21, and CYP11B1 (11ß-hydroxylase) are expressed in this zone. Previous studies demonstrated that human and mouse CYP21 gene promoters contain NBREs, and induction of CYP21 transcription by NGFI-B has been proposed (20, 25). In addition, Bassett et al. (26) recently demonstrated that 3ßHSD2 contains an NBRE in the promoter region and was significantly up-regulated by NGFI-B. On the other hand, NGFI-B had no effect on the induction of CYP11B1 (14) and CYP17 (26), which are not expressed in the zona glomerulosa (2, 23, 27). Therefore, NGFI-B may be partly involved in aldosterone and/or cortisol production through the regulation of some related enzyme expressions in the adrenal cortex and its neoplasms.

In fetal adrenal glands, immunoreactivity of steroidogenic enzymes is known to become generally discernible after 23 wk gestation in the definitive zone (28), and the definitive zone is considered to become steroidogenically active in the late phase of pregnancy (29). However, Nurr1 and NGFI-B immunoreactivities were detected in the definitive zone in all fetal adrenals examined (from 11–36 wk gestational) in our study. Therefore, the expression of Nurr1 and NGFI-B is postulated to occur before the expression of steroidogenic enzymes in the definitive zone in the fetal adrenals. Rainey et al. (30) reported that NGFI-B mRNA expression was very low in the fetal adrenal gland (15–20 wk gestation) compared with that in the adult adrenal by microarray and Northern analyses. These data are not necessarily consistent with our present results, but may be due to the different gestational ages examined or the different examination methods used. In addition, the fact that microarray and/or Northern analysis required a whole adrenal specimen may contribute to this difference from the present immunohistochemical study, because the definitive zone is markedly thin and much smaller in volume than the fetal zone in human adrenal.

Autonomous neoplastic production of cortisol in Cushing’s adenoma or at least some nonfunctioning adenoma patients results in adrenocortical atrophy with suppression of steroidogenic enzyme in the zonae fasciculata/reticularis of the adjacent nonneoplastic adrenocortex through inhibition of ACTH secretion. In addition, the expression of steroidogenic enzymes is markedly decreased, except for CYP21, in the zona glomerulosa of the adjacent nonneoplastic adrenocortex in patients with aldosteronoma (2, 31). Previous in vitro studies demonstrated that Nurr1 and/or NGFI-B were rapidly induced by various factors, including ACTH (32) and angiotensin II (14). However, unexpectedly, Nurr1 and NGFI-B immunoreactivities in the attached nonneoplastic adrenal cortex of adenoma were not significantly different from those in the nonpathological adrenal cortex in our study. It is difficult to explain the mechanisms of these findings, but Davis and Lau (32) reported that NGFI-B isolated from ACTH-stimulated Y-1 cells was hypophosphorylated at serine 354 and significantly bound to its responsive element, whereas NGFI-B present in the unstimulated cells did not. The expression of Nurr1 or NGFI-B was generally considered to be regulated by multiple pathways, and the transcriptional activity is intricately modulated by phosphorylation (24). Therefore, a decrement in steroidogenesis in the attached nonneoplastic adrenal cortex of an adenoma may be partly due to the changes in posttranslational modifications of Nurr1 and/or NGFI-B. Additional examinations are required to clarify this hypothesis.


   Acknowledgments
 
We appreciate the assistance of Ms. Chika Kaneko and Mr. Katsuhiko Ono (Department of Pathology, Tohoku University School of Medicine, respectively) for their skillful technical assistance.


   Footnotes
 
This work was supported in part by NIH Grant DK-43140 (to W.E.R.).

Abbreviations: GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; 3ßHSD2, 3ß-hydroxysteroid dehydrogenase type 2; NBRE, nerve growth factor-induced clone B-responsive element; NGFI-B, nerve growth factor-induced clone B; Nurr1, Nur-related factor 1.

Received January 14, 2004.

Accepted May 5, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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