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Departments of Pathology (T.F., T.S., M.S., M.W., H.S.), Molecular Biology and Applied Physiology (K.T.), and Analytical Medical Technology (K.T.), Tohoku University School of Medicine, Sendai 980-8575, Japan; Kyowa Medex Co., Ltd., Research Laboratory (T.F.), Sizuoka 411-0932, Japan; and Kyowa Hakko Kogyo Co., Ltd., Pharmaceutical Marketing Center (T.N.), Tokyo 100-8185, Japan
Address all correspondence and requests for reprints to: Tsuyoshi Fukuda, Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail: fukuda{at}patholo2.med.tohoku.ac.jp.
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Abstract |
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Objective, Design, and Setting: We examined in situ expression of Ucn and CRF receptors in nonpathological human adrenal gland and its disorders using immunohistochemistry and mRNA in situ hybridization.
Results: Ucn immunoreactivity was localized in the cortex and medulla of nonpathological adrenal glands. Ucn1 immunoreactivity was marked in the medulla, whereas Ucn3 was immunostained mostly in the cortex. Both CRF type 1 and CRF2 were expressed in the cortex, particularly in the zonae fasciculata and reticularis but very weakly or undetectably in the medulla. Immunohistochemistry in serial tissue sections with mirror images revealed that both Ucn3 and CRF2 were colocalized in more than 85% of the adrenocortical cells. mRNA in situ hybridization confirmed these findings above. In fetal adrenals, Ucn and CRF receptors were expressed in both fetal and definitive zones of the cortex. Ucn and CRF receptors were all expressed in the tumor cells of pheochromocytomas, adrenocortical adenomas, and carcinomas, but its positivity was less than that in nonpathological adrenal glands, suggesting that Ucn1, Ucn3, and CRF receptors were down-regulated in these adrenal neoplasms.
Conclusions: Ucn1, Ucn3, and CRF receptors are all expressed in human adrenal cortex and medulla and may play important roles in physiological adrenal functions.
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Introduction |
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Biological actions of CRF family peptides are in general mediated via two types of G protein-coupled receptors, CRF type 1 receptor (CRF1) and CRF type 2 receptor (CRF2) (5, 6). These two receptor subtypes have different physiological functions and are distributed in brain, pituitary, and various peripheral tissues (1, 5, 6, 7, 8, 9). In addition, CRF2 receptor is alternately spliced into three variants with similar binding properties: CRF2(a), CRF2(b), and CRF2(c) (10). Ucn1 is known to bind with high affinity to both CRF1 and CRF2, but this peptide has a 6-fold higher affinity for CRF1 than CRF, and approximately 40-hold higher affinity for CRF2 than CRF (1, 11). Ucn3 was also associated with high affinity for CRF2 but did not bind to CRF1. Ucn1 is expressed in brain, pituitary gland, heart, synovial tissue, reproductive organs, gastrointestinal tract, and so on (1, 7, 8, 9, 12, 13, 14, 15, 16). Ucn3 is also expressed in various tissues including brain, pituitary, heart, kidney, pancreatic ß-cells, and gastrointestinal tract (2, 3, 17, 18, 19). These reports suggest that the CRF system is working against various stress signals throughout the body.
The CRF system coordinates the systemic endocrine responses to stress through its neurohormonal actions as the main physiologic regulator of the hypothalamic-pituitary-adrenal axis (reviewed in Refs.20, 21, 22). Recent studies, which include pharmacological examinations (23, 24), those employing mutant mice with functional deletions in the receptors (25, 26, 27) or CRF (28, 29, 30, 31), the analysis of overproduction of CRF in transgenic mice (32), and the antisense oligodeoxynucleotide technology (33, 34, 35), all suggest that signals through CRF1 and CRF2 act in an antagonistic manner, i.e. CRF1 activates and CRF2 attenuates the stress responses in the central nervous system (reviewed in Refs.20, 21, 22). For example, CRF1 mediates ACTH responses to stress, whereas CRF2 mediates anxiolysis, anorexia, vasodilatation, a positive inotropic action on myocardium, and dearousal (3, 36).
The presence of immunoreactive CRF was reported in human adrenal gland by RIA (37). Expression of Ucn1, Ucn3, CRF1, and CRF2 mRNAs has been also demonstrated in adrenal glands using the RT-PCR method (4, 38, 39). However, it is not known which cell types in adrenal glands express Ucn1, Ucn3, and CRF receptors. Adrenal medulla and pheochromocytomas are also well known to express various kinds of bioactive peptides and their receptors (40, 41). In addition, there is accumulating evidence indicating that adrenal cortex and adrenocortical tumors also express certain kinds of neuropeptides and vasoactive peptides, such as endothelin-1 and adrenomedullin (42, 43), which may regulate the functions of adrenal glands. Furthermore, Sirianni et al. (44) very recently reported that CRF directly stimulated the cortisol biosynthetic pathway in human fetal adrenocortical cells. Therefore, in this study, we examined in situ expression of Ucn1, Ucn3, CRF1, and CRF2 in nonpathological adrenal glands using both immunohistochemistry and mRNA in situ hybridization. We also studied alterations of expression of these peptides in adrenal tumors (adrenocortical tumors and pheochromocytomas) and fetal adrenals to examine possible involvement of these peptides in pathophysiology and development of human adrenal glands.
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Materials and Methods |
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The protocols for this study were approved by the Ethics Committee of Tohoku University School of Medicine (Sendai, Japan). Informed consent from each patient was obtained before collection of any tissue specimens examined in this study.
One hundred two human adrenal specimens were examined in this study. Among these cases, 29 specimens of nonpathological adrenal glands were obtained from autopsy files (16–40 wk gestation, and 7 d to 68 yr of age) from Tohoku University Hospital (Sendai, Japan). Nineteen cases of pheochromocytomas and 54 cases of adrenocortical tumors (nine Cushing’s syndrome, 13 primary aldosteronisms, 10 preclinical Cushing syndrome, nine nonfunctioning adenomas, and 13 carcinomas) were retrieved from the surgical pathology files of Tohoku University Hospital. Preclinical Cushing syndrome was diagnosed according to the criteria reported by Nawata et al. (45). Briefly, in patients with preclinical Cushing syndrome, autonomy of cortisol secretion from the adrenocortical adenoma was detected with a lack of overt clinical signs and symptoms of Cushing syndrome (45, 46). Adrenocortical carcinomas were histologically diagnosed based on the pathological criteria of Weiss (47). These specimens were immediately fixed in 10% formalin for 24–48 h at room temperature and subsequently embedded in paraffin wax.
Antibodies
Properties of antibodies employed in this study were summarized in Table 1
. The Ucn1 and Ucn3 antibodies were produced in our laboratory (the Department of Molecular Biology and Applied Physiology), and its details were previously reported (16, 17). Briefly, a specific antibody against Ucn1 was raised in a rabbit immunized with a peptide corresponding to rat Ucn1 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40) (custom synthesis, Sawady Technology, Tokyo, Japan) conjugated with BSA by glutaraldehyde (16). This Ucn1 antibody completely cross-reacted with human Ucn1 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40) (Peptide Institute Inc., Osaka, Japan) but not with other CRF-related peptides, including CRF or human Ucn3 in RIA. A specific antibody against Ucn3 was raised in a rabbit by injecting tyrosyl-Ucn3 (custom synthesis, Sawady Technology) conjugated with BSA by carbodiimide (Peptide Institute) (17). RIA analysis using this Ucn3 antibody demonstrated less than 0.001% cross-reaction with CRF, Ucn1, and other peptides examined (17). The specificity of the Ucn1 and Ucn3 antibodies was also confirmed by the absorption test using the synthetic peptides in immunohistochemistry (7, 8, 9, 15, 17). Anti-chromogranin A (CgA) was purchased from Dako (Carpinteria, CA; catalog no. M0869), anti-CRF1 was purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA; catalog no. sc-12381), and anti-CRF2 was purchased from Abcam Ltd. (Cambridge, UK (catalog no. ab12964).
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Immunohistochemistry was performed using the avidin-biotin signaling system using Histofine kit (for CRF1 and CRF2; Nichirei, Tokyo, Japan) and the polymer signal amplification system using EnVision kit (for Ucn1 and Ucn3; Dako). After deparaffinization, antigen retrieval was performed by heating in an autoclave at 120 C for 5 min in citric acid buffer [2 mM citric acid and 9 mM trisodium citrate dehydrate (pH6.0)] and then allowed to cool down for approximately 1 h at room temperature. The slides were treated with 1% normal goat (Ucn1, Ucn3, and CRF2) or rabbit serum (CRF1) for 30 min at room temperature in a moisture chamber. Primary antibodies (optimal dilution; 1:1000 for Ucn1, 1:2000 for Ucn3, 1:250 for CRF1, and 1:1000 for CRF2) were applied on the tissue sections for 18 h at 4 C. For blocking internal peroxidase reaction, the slides were treated in 0.3% H2O2/methanol buffer. Secondary antibody conjugated peroxidase with polymer linker was applied on the slides for 30–60 min at room temperature (Ucn1 and Ucn3). Antigoat IgG rabbit (CRF1) or antimouse IgG goat (CRF2) polyclonal antibody conjugated with biotin was applied on the slides for 30 min at room temperature. For CRF1 and CRF2, avidin-peroxidase conjugate was applied in these slides for 30 min at room temperature. The antigen-antibody conjugate was subsequently visualized with 3,3'-diaminobenzidine (DAB) solution [1 mM 3,3'-diaminobenzidine, 50 mM Tris-HCl buffer (pH7.6), and 0.006% H2O2] and counterstained with hematoxylin. An absorption test for Ucn1 and Ucn3 was performed to confirm the specificity of immunoreactivity. Antibody-antigen mixtures containing Ucn1 antibody and Ucn1 peptide or Ucn3 antibody and Ucn3 peptide (final concentration: 20 µmol/liter) were incubated at 4 C for 18 h. After centrifugation, supernatants were used as absorbed antibodies. An intensity of immunostaining was classified in the cytoplasm and was evaluated on a scale of 0–2 (0, negative; 1, weakly positive; 2, positive; 0 and 2 corresponded to the absence and highest degree of staining, respectively). All specimens were evaluated by two of the authors (T.F. and T.S.) independently.
mRNA in situ hybridization
Three nonpathological human adrenal tissue specimens were used for mRNA in situ hybridization. mRNA in situ hybridization was performed using the Discovery system (Ventana Medical Systems, Inc., Tucson, AZ) as previously described (9). A probe for Ucn1 was prepared from pSPT19-Ucn1, as previously reported (9). Ucn3 cDNA (a 469-bp fragment corresponding to 5/473 of the Gene Bank accession no. AF361943) was amplified from total RNA of human adrenal by RT-PCR (19). The PCR product was ligated to pSPT19 vector (Roche Diagnostics, Mannheim, Germany), yielding the subclone pSPT19-Ucn3. The nucleotide sequence was determined using a model 373A autosequencer (PerkinElmer, Chiba, Japan) and was confirmed to be identical with the registered sequence. The plasmid was linealized by the digestion with EcoR1 (for antisense probe) or HindIII (for sense probe). Digoxigenin-labeled RNA probe was generated with digoxigenin-RNA labeling kit (Roche Diagnostics) following the manufacturer’s instruction.
Duplicated slides were loaded onto Discovery automated slide-processing system. Baking and deparaffinization steps were performed as programed in the protocol for the RiboMap in situ hybridization regent system (Ventana Medical Systems) on the instrument. After deparaffinization step, protocols for mRNA in situ hybridization were designed based on the standard protocols of RiboMap kit (Ventana Medical Systems). The first fixation step was performed using formalin-based RiboPrep reagent (Ventana Medical Systems) for 30 min at 37 C. Fixed sections were acid treated using hydrochloride-based RiboClear reagent (Ventana Medical Systems) for 10 min at 37 C. The slides were subsequently incubated to protease digestion using protease 2 (Ventana Medical Systems) for 2 min at 37 C. After a denaturing step for 10 min at 70 C, the incubated slides were reacted for hybridization with Ucn1 (3 ng/slide), Ucn3 (100 ng/slide), antisense or sense RNA probe-diluted RiboHybe hybridization buffer (Ventana Medical Systems) for 6 h at 65 C. Hybridized sections were washed in three stringency steps using 0.1x RiboWash (Ventana Medical Systems) for 6 min each at 65 C; the second fixation step was performed using RiboPrep reagent for 20 min at 37 C followed by incubation of biotin-labeled antidigoxigenin antibody (Sigma-Aldrich, Inc., St. Louis, MO) for 30 min at 37 C. The slides were incubated with streptavidin-alkaline phosphatase conjugate for 16 min at 37 C. The signal was subsequently detected automatically using BlueMap 4-nitro blue tetrazolium chloride/5-bromo-4-chloro-3-indoyl-phosphate, 4-toluidine salt substrate kit for 6 h at 37 C. The slides were counterstained with Fast Red for 5 min before mounting.
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Nonpathological adrenal glands.
In nonpathological adrenals, Ucn1 immunoreactivity was marked in the adrenal medulla in all 14 cases of human adrenal glands examined. Immunoreactive Ucn1 was also detected in the adrenal cortex, although their relative immunointensity was weak in the great majority of the cases (Fig. 1A). Ucn3 immunoreactivity was diffusely present in all three zones of adrenal cortex in all the cases examined but weakly positive in the adrenal medulla in 10 of 14 cases and negative in three cases (Fig. 1B). Immunostaining of CgA, which is a marker of adrenal medullary cells, in serial tissue sections confirmed that Ucn1 immunopositive cells in adrenal medulla were identical with those of CgA-positive cells (Fig. 1, A and C). Immunoreactivities for both CRF1 and CRF2 were marked in nonpathological adrenal glands, especially in zonae fasciculata and reticularis (Fig. 1, D and E). Immunoreactivities for CRF1 and CRF2 were also detected in the zona glomerulosa, but their relative immunointensity was weaker than that in the other two zones of the adrenal cortex. In adrenal medulla, CRF1 and CRF2 immunoreactivity was weak or undetectable. Results of immunoreactivity for Ucn1, Ucn3, CRF1, and CRF2 in nonpathological adrenal are summarized in Table 2. We subsequently analyzed serial tissue sections with mirror image for immunohistochemistry of Ucn3 and CRF2 in three nonpathological adrenal cases to clarify the colocalization of Ucn3 and CRF2 in the same adrenocortical parenchymal cells (Fig. 1, F and G). Ucn3 and CRF2 were colocalized in more than 85% adrenal cortical cells. Mirror image analysis in serial tissue sections demonstrated that both CRF1 and CRF2 were also coexpressed in more than 70% adrenal cortical cells (data not shown).
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Immunoreactivity for Ucn1, Ucn3, CRF1, or CRF2 was not detected in 16 wk (data not shown). Immunoreactivities for Ucn1 and Ucn3 were detected mainly in fetal zone in 20 wk (Fig. 2, A and B) and in both fetal and definitive zones in 37 wk (Fig. 2, E and F). Ucn1 immunoreactivity was, however, not detectable in fetal adrenal cortex of 39 gestational weeks (Fig. 2I), whereas immunoreactivity for Ucn 3 was detected in the same adrenal specimens (Fig. 2J). In fetal adrenal cortex, immunoreactivity for CRF1 was detected in both fetal and definitive zones starting from 20 to 37 wk gestation (Fig. 2, C and G). Immunoreactivity for CRF2 was weakly detected in fetal zone from 20 to 37 wk gestation (Fig. 2, D and H).
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Ucn1 and Ucn3 immunoreactivity was detected in the tumor cells of pheochromocytomas in 13 and 10 of 19 cases, respectively (Table 3 and Fig. 3). In attached nonneoplastic adrenal, Ucn1 immunoreactivity was marked in nonneoplastic medulla (Fig. 3B), whereas Ucn3 was detected both in adrenal cortex and medulla, with more marked immunoreactivity in the cortex (Fig. 3D). This finding is consistent with that in nonpathological adrenal glands illustrated in Fig. 1
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, E and G). CRF1 and CRF2 immunoreactivity was also detected in attached nonneoplastic adrenal cortex but very weakly or undetectable in the medulla (Fig. 3, F and H), consistent with the findings in nonpathological adrenal gland (Fig. 1). Adrenocortical adenomas and carcinomas
Ucn1 and Ucn3 immunoreactivity was detected in approximately half of adrenocortical adenoma cases examined (Cushing syndrome, preclinical Cushing syndrome, primary aldosteronism, and nonfunctioning adenomas), although their relative immunoreacitivity was weak in the great majority of the cases (Table 3 and Fig. 4). Ucn1 and Ucn3 immunoreactivity was detected in attached nonneoplastic adrenal (Fig. 4, B and D), and their patterns of their immunoreactivity were similar to those of nonpathological adrenal glands (Fig. 1) expect for those associated with Cushing syndrome or preclinical Cushing syndrome, whose attached nonneoplastic adrenals were atrophic.
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). Their immunoreactivity was also detected in attached nonneoplastic adrenal (Fig. 4, F and H) as in nonpathological adrenal glands (Fig. 1) expect for those associated with Cushing syndrome or preclinical Cushing syndrome, whose attached nonneoplastic adrenal were atrophic.
Immunoreactivity for Ucn1, Ucn3, CRF1, and CRF2 was all detected in adrenocortical carcinomas with less frequency of positivity than nonpathological adrenal glands as in adrenocortical adenomas (Table 3).
mRNA in situ hybridization
Accumulation of mRNA hybridization signals for Ucn1 mRNA was marked in medulla but weakly or not detected in cortex of nonpathological adrenal glands (Fig. 5A). Hybridization signals for Ucn3 mRNA were also detected in the adrenal cortex (Fig. 5C), which is consistent with results in immunohistochemistry. Ucn 3 mRNA signals were not detected in the adrenal medulla (data not shown) despite positive immunostaining of Ucn3 in the adrenal medulla (Fig. 1B), possibly because the sensitivity of in situ hybridization used in our study was lower than that of immunohistochemistry. Negative controls using sense probes for Ucn1 and Ucn3 mRNAs yielded no significant accumulation of mRNA hybridization signals of those peptides (Fig. 5, B and C).
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Discussion |
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, A and B). These findings all suggest autocrine and/or paracrine roles of Ucn1 and Ucn3 in functional regulation of nonpathological human adrenal glands (Fig. 6). CRF was reported to be expressed in adrenal medulla and tumors derived from the medulla (37, 48, 49), which suggest that the CRF system is locally exerting their effects in human adrenal glands. Results of our present study also raised the possibility that Ucn1 secreted from adrenal medulla may play an important role in a possible interaction between adrenal cortex and medulla. Adrenal medulla has also been well known to produce ACTH (50). It is therefore tempting to postulate that Ucn1 secreted by the adrenal medulla may act on CRF1 in the medulla and stimulate the secretion of ACTH, which may subsequently act on adrenal cortex. In addition, Bornstein and Ehrhart-Bornstein (51) recently proposed regulation of adrenal steroidogenesis through intraadrenal mechanisms. Ucn1 secreted from the adrenal medulla may therefore also act on CRF receptors expressed in the cortex. On the other hand, Ucn3 secreted from adrenal cortex, as well as Ucn1, may act on CRF2 present in the adrenal cortex in paracrine and/or autocrine manners. Results of our present analysis of immunohistochemistry in serial tissue sections with mirror images, which makes it possible to study expression of two different proteins in the same cells, demonstrated that Ucn3 and CRF2 were colocalized in more than 85% adrenal cortical parenchymal cells (Fig. 1, F and G), which is consistent with the putative roles of Ucn3 discussed above.
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In fetal adrenal cortex, patterns of expression of Ucn1, Ucn3, and CRF receptors changed dynamically from early stage to birth. Ucn1 was expressed in both fetal and definitive zones in midfetal stage (Fig. 2, A and E), but before birth (39 wk), Ucn1 was not expressed in fetal adrenal cortex (Fig. 2I). After birth, Ucn1 was expressed in infant adrenal medulla (data not shown). Ucn1 expression may therefore be induced by some stress at birth. Ucn3 was expressed in both fetal and definitive zone (Fig. 2, B, F, and J), suggesting that Ucn3 was continuitively expressed from immature to mature adrenal cortex. Furthermore, CRF1 was markedly expressed in both fetal and definitive zones (Fig. 2, C and G). In fetal stage, both CRF and Ucn1 are secreted from placenta (55, 56, 57). It was reported that CRF controlled synthesis and secretion of adrenocortical hormones, including dehydroepiandrosterone sulfate and cortisol, in human fetal adrenal (44, 58, 59). Both CRF and Ucn1 secreted by placenta, as well as Ucn1 produced locally in the adrenal gland, may act on CRF1 expressed in fetal zone of adrenal. On the other hand, the weak expression of CRF2 in fetal zone may be explained by the fact that stresscoping actions mediated by CRF2 may not be essential during the fetal period.
Reubi et al. (60) reported that the tumors including pituitary adenomas and central and peripheral nervous system tumors expressed CRF receptors, whereas other tumors including ductal pancreatic, prostatic, colorectal, and non-small cell lung cancers lacked CRF receptors. In our present study, Ucn1, Ucn3, CRF1, and CRF2 were all detected in tumor tissues of adrenocortical tumors (adenomas and carcinomas) and pheochromocytomas (Figs. 3 and 4). The positive ratios and relative immunointensity of these adrenal neoplasms examined in our present study were, however, not as high as those in nonpathological adrenal glands. These findings suggest that the intraadrenal CRF system was possibly down-regulated in both cortical and medullary neoplasms.
In summary, Ucn1, Ucn3, and CRF receptors were all expressed in nonpathological human adrenal cortex and medulla. These findings raised the possibility that Ucn1 and Ucn3 form intraadrenal CRF system together with CRF and may regulate adrenocortical functions in the autocrine/paracrine fashion and in a possible interaction between cortex and medulla (Fig. 6).
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Acknowledgments |
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Footnotes |
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First Published Online May 24, 2005
Abbreviations: CgA, Chromogranin A; CRF, corticotropin-releasing factor; CRF1, CRF type 1 receptor; CRF2, CRF type 2 receptor; DAB, diaminobenzidine; SCP, stresscopin; Ucn1, urocortin 1; Ucn3, urocortin 3.
Received January 14, 2005.
Accepted May 16, 2005.
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