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Population Council (M.K., P.L.M) and The Rockefeller University (P.L.M.), New York, New York 10021
Address all correspondence and requests for reprints to: Dr. Patricia L. Morris, Center for Biomedical Research, Population Council and The Rockefeller University, 1230 York Avenue, New York, New York 10021. E-mail: p-morris{at}popcbr.rockefeller.edu
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Abstract |
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(IFN)
markedly inhibits GH-stimulated StAR mRNA and protein levels. When
cells are cultured with both GH and IFN, IFN decreases the
stimulating effect of GH on androgen production. Treatment of PLCs with
cycloheximide does not prevent the GH-induced StAR mRNA, indicating
that GH induction of StAR transcripts does not require de
novo protein synthesis. In contrast, the induction of 3ß-HSD
mRNA by GH is altered by cycloheximide treatment. H7, a
serine/threonine kinase inhibitor, completely abrogates the increases
in StAR mRNA by GH, whereas the tyrosine kinase inhibitor genistein
does not. Moreover, GH further enhances StAR and 3ß-HSD mRNA
expression in isolated adult rat Leydig cells despite their increased
basal expression subsequent to maturational acquisition of these
steroidogenic components. These data provide the first demonstration of
the direct effects of GH on testicular steroidogenesis during
progenitor Leydig cell differentiation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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During the prepubertal period, three well defined developmental stages
of Leydig cells are observed in the rat testis (7, 8). Mesenchymal stem
cells proliferate and differentiate into progenitor Leydig cells
(PLCs), which predominate in the testis from days 14–21. In
vivo, PLCs subsequently acquire the characteristics of immature
Leydig cells (ILCs), which produce preferentially the androgen,
androstane-3
,17ß-diol (3-DIOL), rather than the testosterone
reflective of the adult Leydig cell (ALC). ILCs then undergo an
additional round of proliferation and begin to terminally differentiate
into nondividing ALCs. ALCs are distinguished from their immature
precursors by a higher abundance of LH receptors (LHR), the predominant
expression and activity of 
5-3ß-hydroxysteroid
dehydrogenase (3ß-HSD) rather than the 3-HSD characteristic of
PLCs and ILCs, and increased production of testosterone. These
maturational characteristics of PLC, ILC, and ALC are typified at 21,
35, and 55–90 days in the rat, respectively.
The acute response of steroidogenic cells to tropic hormone stimulation
is a rapid increase in the rate of steroid hormone biosynthesis (9).
The process involves at least two mechanisms. The first part of the
process is transport of cholesterol substrate to the inner
mitochondrial membrane, a process that involves steroidogenic acute
regulatory protein (StAR), the peripheral benzodiazepine receptor and
its ligand, and potentially other mediators. The second part of the
process is the metabolism of cholesterol into testosterone, which
requires several different steroidogenic enzymes, including cytochrome
P450 side-chain cleavage (P450scc) and 3ß-HSD enzymes activities.
P450scc converts transported cholesterol to pregnenolone, and 3ß-HSD
is involved in the conversion of pregnenolone to progesterone. In
adrenal cells, 3ß-HSD is expressed not only in smooth endoplastic
reticulum but also in the mitochondria, where it is associated with
StAR and P450scc (10). StAR messenger RNA (mRNA) and protein are
induced concomitantly via a cAMP-mediated mechanism in the MA-10 Leydig
cell line (9, 11). In the hypophysectomized sheep corpus luteum
in vivo, StAR gene expression is stimulated by treatment
with either of the tropic hormones LH or GH (12). Chronic treatment (48
h) with IGF-I is required to increase StAR expression in cultured
porcine granulosa cells (13). Recent studies showed that pretreatment
with the cytokines interferon- (IFN) (24 h) and tumor necrosis
factor- (48 h) decreased hCG-induced StAR expression in primary
Leydig cells (14, 15).
In this study, we examined the ontogeny of GH receptor (GHR) and StAR mRNA expression in purified Leydig cells at different maturational stages, and the effect of GH on the level of StAR expression and androgen production in vitro. To our knowledge, these data provide the first evidence for a direct effect of GH on testicular steroidogenesis and specific steroidogenic components during Leydig cell development.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-HSD immunocytochemistry and 3ß-HSD histochemistry as we
previously described (6). PLCs were 45% 3-HSD positive and 42%
3ß-HSD positive after 2 days of culture. Both cultured ILCs and ALCs
were found to average over 90% and 97% 3ß-HSD positive,
respectively. Leydig cells were cultured for 2 days in serum-free
medium supplemented with 2.5 µg/ml insulin (Sigma Chemical Co., St. Louis, MO), 5 µg/ml transferrin
(Calbiochem, La Jolla, CA), and 10 µg/ml bacitracin
(Sigma Chemical Co.). Cells were rinsed and then
pretreated with or without cycloheximide (CHX; Calbiochem)
or kinase inhibitors (H7 or genistein; Calbiochem) as
indicated. After removal of the pretreatment-containing media and
several rinses with the addition of fresh serum-free media, cells were
stimulated with hCG (13,000 mIU/mg; a gift from Y. Y. Tsong, The
Population Council), ovine GH (NIDDK oGH-15), rat PRL (NIDDK
rPRL-B8SIAFP), or rat IFN (Genzyme Corp., Cambridge,
MA) for the indicated times and dosages. The media were then collected
and stored at -20 C until the measurement of 3-DIOL and
testosterone by specific RIAs with either anti-3-DIOL (3%
cross-reactivity with testosterone; Miles Scientific, Naperville, IL)
or anti-testosterone (<1% cross-reactivity with 3-DIOL; gift
from Dr. G. D. Niswender, Colorado State University, Boulder, CO)
antiserum (17). Purified steroids for use as RIA standards were
obtained from Steraloids (Wilton, NH). Procedures involving the use of
animals strictly followed the Guidelines for the Care and Use of
Laboratory Animals set forth by the NIH. The MA-10 cell line (provided
by M. Ascoli, University of Iowa, Iowa City, IA) used in these
experiments was maintained as previously reported (6).
Northern blot analysis
RNA isolation and Northern blot analyses were performed using
methods we previously described (18). Mouse 3ß-HSD (892-bp) or rat
GHR (533-bp) complementary DNA (cDNA) was amplified by the RT-PCR
method using previously described primers as reported (19, 20, 21) and the
cDNAs cloned into pPCR-Script plasmid (Stratagene, La
Jolla, CA). 3ß-HSD is a member of a multigene family, and the probe
used in this study was designed to recognize several of the rat
isoforms, including the type I and type II isoforms expressed
exclusively in the testis (19, 22). The sequences of mouse 3ß-HSD
cDNA probe (GenBank M58567) is 91% identical to both rat type I
(M38178) and type II (M38179) 3ß-HSD mRNA. Mouse StAR (1.5 kb;
provided by Dr. D. M. Stocco), mouse 3ß-HSD, rat GHR, or human
G3PDH (CLONTECH Laboratories, Inc., Palo Alto, CA) cDNAs
were labeled with [-32P]deoxy-CTP (Amersham, Arlington
Heights, IL) using random hexamers. The filters were exposed to Kodak
X-Omat AR film (Eastman Kodak Co., Rochester, NY), and
signals were evaluated using PhosphorImager (Molecular Dynamics, Inc., Sunnyvale, CA) analyses.
Immunoblot analysis
Mitochondrial protein was isolated from cultured PLCs treated
with or without reagents using TSE buffer containing 0.25 M
sucrose, 10 mM Tris (pH 7.4), and 0.1 mM EDTA
as previously described (11). The protein concentration was determined
by the Bradford assay. Mitochondrial proteins (50 µg/lane) were
subjected to SDS-PAGE using 12% polyacrylamide gels and transferred to
a nitrocellulose membrane (Schleicher & Schuell, Inc.,
Keene, NH). The membrane was probed with a specific mouse polyclonal
antiserum raised against a 10-amino acid peptide (88–98) of the StAR
protein (provided by Dr. D. M. Stocco). Blots were developed using
an enhanced chemiluminescence Western blotting system (Amersham).
Data analysis
All experiments were repeated at least three times using
separate primary cell preparations. The results presented are typical
for each experiment illustrated. The significance of the results was
determined using Student’s t test and ANOVA, followed by
a posteriori testing using Dunnett’s or Tukey-Kramer
multiple comparison test as required. P 
0.05 was
considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and 3ß-HSD have been shown to be appropriate
markers of the maturational status of Leydig cell (6, 7, 8, 16, 17).
Therefore, detection of 3ß-HSD mRNA was used as one parameter of the
developmental and steroidogenic status of the cultured Leydig cells in
this study. As anticipated, the levels of 3ß-HSD mRNA (1.7 kb)
increased with the age of the rats used and paralleled Leydig cell
differentiation. The same Northern filters were stripped and
rehybridized with StAR, GHR, and G3PDH cDNA probes. Two species of mRNA
(3.8 and 1.7 kb) from Leydig cells hybridized to the StAR cDNA probe.
PLCs demonstrated low signals for StAR transcripts, whereas intense
signals appeared in ILCs and ALCs. In rodents, GHR mRNA exists in two
forms, one encoding the hormone-binding domain common to the GHR and
the other encoding the soluble GH-binding protein (GHBP). Hybridization
of GHR cDNA showed that a 1.3-kb band corresponding to GHBP mRNA was
clearly detected, whereas a GHR band (4.3-kb) was faintly observed in
PLCs. In contrast, low levels of GHBP mRNA were demonstrated in ILCs
and ALCs (Fig. 1
).
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). GH (100 ng/ml) as well as hCG
(100 ng/ml) increased StAR transcripts within 3 h, whereas 100
ng/ml PRL had no effect within 18 h. By rehybridizing the same
membrane with a 3ß-HSD cDNA probe, we determined the levels of
3ß-HSD. Induction of 3ß-HSD transcripts was also seen after both GH
and hCG treatment, but the effect of PRL treatment was not different
from that of the vehicle blank control treatment. Next, various
concentrations of GH (0.1–500 ng/ml) were added for 3 h to the
PLCs, and changes in StAR mRNA levels were determined. The addition of
GH at increasing doses resulted in a dose-dependent increase in the
levels of StAR mRNAs (Fig. 2B). Although IFN (10 ng/ml) had no
effect on the basal level of StAR gene expression (Fig. 2A), IFN
inhibited GH-induced StAR mRNA expression within 3 h (Fig. 2C).
Western blot analyses showed that GH as well as hCG induces StAR
protein expression, and that IFN inhibits the stimulation by GH,
data consistent with the changes in mRNA levels from Northern blot
analyses (Fig. 2D).
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-DIOL) in PLCs treated with hCG (100 ng/ml), GH (100 ng/ml),
and/or IFN (10 ng/ml) for 18 h (Fig. 3). GH as well as hCG increased steroid
production (P < 0.01 compared with the control value).
IFN alone appeared to decrease androgen production, but not at a
statistically significant level (P > 0.05 compared
with the control value). When cells were cultured with both GH and
IFN, IFN decreased the stimulating effect of GH on PLC androgen
production (P < 0.05 compared with the value with GH
alone treatment).
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).
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). ALCs were cultured for 2
days, and then treated with either 100 ng/ml hCG or GH. Both GH and hCG
increased the levels of StAR and 3ß-HSD gene expression in ALCs.
Although temporally GH initially induced the 1.7-kb band of StAR in
PLCs (Fig. 2
), increases in the 3.8-kb transcript were first seen at
3 h after GH or hCG treatment in ALCs (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-HSD and 5-reductase) and testosterone biosynthetic
enzymes (3ß-HSD, P450scc, and P450c17) (9). In an ALC, testosterone
production is 150 times greater than that in a PLC and 5 times greater
than that in an ILC (8). In addition to changes in these enzymes, we
now show that basal levels of StAR gene expression are greatly
increased in ILCs and ALCs compared with those in PLCs. Other recent
studies reported that StAR protein is undetectable in freshly isolated
immature Leydig cells, but is easily detectable in those prepared from
adult rats (25). Differences in the findings between this study and
ours may reflect the methodologies used. The increasing capacity for
testosterone production in developing Leydig cells may be concordant
with rising levels of StAR protein, which regulate cholesterol
transport in mitochondria.
Our present data imply that GH is involved in the functional
development of Leydig cells in vivo. However, direct or
indirect effects of GH have never been clearly established in the
Leydig cell. This remains unresolved due in part to issues associated
with defining the actions of GH on the Leydig cell, namely the ability
of human GH to bind to both somatogenic (GH) and lactogenic (PRL)
receptors. In this study, ovine GH, but not rat PRL (both in 100 ng/ml
doses), stimulated StAR and 3ß-HSD mRNAs in PLCs despite the presence
of PRL receptors in the immature rat testis (26, 27, 28). Many of the
actions of GH are thought to be mediated by IGF-I. Although a previous
study showed that bovine GH increased testicular IGF-I mRNAs in
immature hypophysectomized rats (4), these investigators were unable to
detect GHR in the rat testis and suggested that the effects of GH were
indirect. A later immunohistochemical study showed the localization of
GHR protein in the Leydig and Sertoli cells of the adult rat testis
(29). We now demonstrate the expression of GHR mRNA in purified
progenitor, immature, and adult Leydig cells. Taken together with our
recent study (6), these findings are suggestive of a functional GH
signaling pathway in the Leydig cell. Additionally, pretreatment of
PLCs with CHX did not prevent the GH-stimulated elevation in the levels
of StAR mRNA, indicating that GH induction of StAR transcripts is
direct and does not require de novo protein synthesis. GHR
is preferentially expressed in PLCs compared with the mRNA levels in
ILCs and ALCs. In contrast, the levels of LHR mRNA and hCG-binding
sites in ILCs and ALCs are higher than those in PLCs (30). The relative
scarcity of LHR in PLCs indicates that additional hormones and factors
may be important in the initial phase of Leydig cell differentiation
in vivo. In male rats, episodic GH secretion is established
during the prepubertal period (at about 22 days of life) with the
presence of peaks of GH of low amplitude (31). In rats, 5-reduced
metabolites, 3-DIOL, and androsterone are abundant in the
circulation between days 20–40 postpartum when the testosterone level
is still low (32). These data imply that GH may play an important role
in Leydig cell differentiation or proliferation during the prepubertal
period. Additionally, our data suggest that the GHR is functional in
ALCs despite the low level of its expression, and that testosterone
production can be further increased upon GH stimulation.
Several studies imply that IFN plays a negative role in testicular
steroidogenesis (14, 33, 34, 35). We recently showed that the mRNA and
protein for IFN receptor (IFNR) - and ß-chains are expressed
in isolated rat Leydig and Sertoli cells (18). In cultured porcine
Leydig cells, IFN treatment inhibits gonadotropin-stimulated
testosterone production as well as the level of mRNAs for steroidogenic
enzymes (33). Inhibitory effects of IFN can be partially or
completely reversed by the addition of cholesterol analogs that can be
used as substrate for P450, indicating that IFN also affects early
events in cholesterol transport before the side-chain cleavage of
cholesterol (14, 33). In addition, pretreatment of rat ALCs by IFN
for 24 h inhibits hCG-stimulated Leydig cell steroidogenesis by
the down-regulation of StAR expression (14). Our data demonstrate that
IFN has an acute inhibitory effect on GH-induced StAR mRNA and
protein levels. Chronic administration of IFN to mice results in
reduced testicular weights, decreased sperm count and concentration,
and abnormalities in sperm morphology (35). Our previous findings
showed that IFNRs are functional in rat Sertoli cells (36, 37).
Taken together, these findings suggest that chronic IFN-induced
effects on spermatogenesis are mediated by both Leydig and Sertoli
cells in vivo. Furthermore, CHX or genistein pretreatment
enhances the GH induction of StAR mRNA in this study, indicating the
putative involvement of inhibitors that require tyrosine
phosphorylation and/or new protein synthesis, respectively, on StAR
expression.
In this study, H7, a broad-based serine/threonine kinase inhibitor, altered GH-induced StAR mRNA in PLCs. H7 inhibits protein kinase A, C, and G and myosin light chain kinase. Phosphorylation of StAR protein on a threonine residue is required for the acute induction of steroidogenesis in MA-10 mouse Leydig tumor cells (38). We recently showed that GH can act directly on rat Leydig cells by phosphorylation of STAT-5b. GH stimulated DNA binding of STAT-5b in immature (18-day-old) Leydig cells, but not in ALCs (6). However, StAR mRNAs were induced in both PLCs and ALCs. Furthermore, genistein pretreatment did not block the induction of StAR transcripts in PLCs, while tyrosine phosphorylation of the Janus kinase (JAK)/STAT pathway is required for STAT-5b activation by GH in Leydig cells (6). Therefore, it is less likely that the effect of GH on StAR expression is mediated by the JAK/STAT-5b cascade. In addition to the STAT, mitogen-activated protein kinase, and Ras-dependent pathways that are linked to the tyrosine phosphorylation of JAK2, GH signals are transduced via voltage-dependent Ca2+ channels, phospholipase C, protein kinase C (PKC), insulin receptor substrate 1, and cytosolic phospholipase A2 (39, 40, 41, 42). Treatment with phorbol 12-myristate 13-acetate, a pharmacological activator of PKC, eliminates the FSH induction of StAR mRNA in luteinized porcine granulosa cells, indicating that PKC is unlikely to be an intermediary in the GH-dependent stimulation of the StAR gene (13). Similar to the steroid hydroxylase genes, consensus cAMP-responsive elements are not present in the StAR promoter region (43). The roles of LH and subsequent increases in cAMP in mediating StAR gene transcription by steroidogenic factor 1, an orphan nuclear receptor, have been investigated (44, 45). Further work is needed to determine the signaling pathway(s) activated by GH during the induction of the StAR gene in Leydig cells.
In conclusion, GH directly increases the levels of StAR mRNA and
protein expression through GHR, but not PRL receptor, in Leydig cells.
Additionally, IFN inhibits GH-stimulated StAR levels and steroid
production in both basal and GH-stimulated PLCs. Thus, our studies are
consistent with an important role for an additional pituitary hormone,
namely GH, in the pubertal acquisition of steroidogenic ability.
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Acknowledgments |
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Footnotes |
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Received October 2, 1998.
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References |
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inhibits the steroidogenic acute regulatory protein messenger
ribonucleic acid expression and protein levels in primary culture of
rat Leydig cells. Endocrinology 139:2217–2222 inhibits
Leydig cell steroidogenesis through a decrease in steroidogenic acute
regulatory protein expression. Endocrinology 139:2863–2868-androstan-17ß-ol-3-one to
5-androstane-3,17ß-diol and 5-androstane-3ß,17ß-diol by
rat testicular cells in vitro. J Reprod Fertil 57:143–147[Abstract]
(IFN) receptor subunits:
IFN enhances interferon regulatory factor-1 and interleukin-1ß
converting enzyme expression. Endocrinology 139:2636–2644-hydroxylase/C17–20 lyase, and P450 aromatase in
fetal mouse gonads. Endocrinology 135:262–268[Abstract]
5-4 isomerase cDNAs and
differential tissue-specific expression of the corresponding mRNAs in
steroidogenic and periferal tissues. J Biol Chem 266:583–593-androstane-3,17ß-diol, androsterone, and testosterone
concentration in the male rat. Influence of age and gonadotropin
stimulation. Endocrinology 100:1027–1032[Abstract]
inhibits steroidogenesis and accumulation of mRNA of the steroidogenic
enzymes P450scc and P450c17 in cultured porcine Leydig cells. Mol
Endocrinol 3:887–894[Abstract]
. Reprod Toxicol 10:379–391[CrossRef][Medline]
in Sertoli cells. Endocrinology 137:4738–4743[Abstract]
is mediated through phosphorylation of STAT-3 and STAT-1
proteins. Endocrinology 138:2740–2746This article has been cited by other articles:
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