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and -
in Testicular Interstitial Tissue and Spermatogonia of the Rat1
GERM-INSERM U-435, Université de Rennes I, Campus de Beaulieu, 35 042 Rennes, Bretagne, France
Address all correspondence and requests for reprints to: Dr. Bernard Jégou, GERM-INSERM U-435, Université de Rennes I, Campus de Beaulieu, 35 042 Rennes Cedex, Bretagne, France. E-mail: bernard.jegou{at}rennes.inserm.fr
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study we searched for IFN production by Leydig cells,
testicular macrophages, and spermatogonia after exposure to Sendai
virus. We also investigated the effect of viral exposure on
testosterone production by Leydig cells. Our results show that
spermatogonia do not constitutively express IFNs and give a very poor
response to the virus. In contrast, testicular macrophages
constitutively produced type I IFNs, and this production was markedly
stimulated by Sendai virus. Leydig cells produced twice as much type I
IFNs as testicular macrophages after viral exposure, and they were the
only cells producing both IFN
and -
, with these IFNs being
dramatically induced/increased in response to exposure to the virus.
Furthermore, incubation of Leydig cells with the Sendai virus
stimulated testosterone production. In conclusion, this study further
establishes the topography of IFN expression within the testis. This
allows us to hypothesize that the potential antiviral system
represented by Leydig cells and, to a lesser extent, by macrophages
plays a key role in protecting both androgen production and
spermatogenesis.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Interferons (IFNs) are small proteins known for their antiproliferative
and immunoregulatory activities and their crucial involvement in
cellular antiviral action (4). There are two types: type I IFNs
(IFNs, IFNß, IFN
, and IFN
) and type II IFN or IFN. In a
previous series of experiments, we searched for IFN secretion and,
hence, antiviral capability within the seminiferous tubule (5). This
work was prompted by studies suggesting the involvement of IFNs in
spermatogenesis regulation (6, 7, 8) and the lack of studies focusing on
the increase in sexually transmissible viral diseases. We demonstrated
that peritubular and Sertoli cells, the somatic constituents of the
tubules, secrete substantial levels of type I IFNs in response to viral
infection. In contrast, the meiotic pachytene spermatocytes and the
postmeiotic haploid early spermatids produce low levels of type I IFNs
constitutively. This production is either not affected or is only
slightly enhanced by exposure to Sendai virus. It is important to know
how the seminiferous compartment is equipped to react to viral attack,
as some sexually transmissible viral infections [mumps and human
immunodeficiency virus (HIV)] can lead to azoospermia and sterility
(9, 10). However, it is possible that the first line of testicular
antiviral defense may be located in the interstitial compartment. This
compartment is the original site of virus entry from the blood vessels,
and different virus types have been located in Leydig cells (11, 12, 13).
Leydig cells have a key paracrine and endocrine role and, thus, may be
expected to provide maximal protection against viral attack. We,
therefore, studied the reactions to viral exposure of the two main
cellular components of the interstitium, namely macrophages and Leydig
cells. As spermatogonia, the germ cell precursors, are located within
the basal compartment of the seminiferous tubule (2, 3), they are
exposed to the components present in testicular lymph. Thus, we also
investigated their response to viral exposure. The main objective of
the present in vitro study was to search for IFN production
by cells in basal conditions of culture and after viral stimulation
using a range of techniques, including RT-PCR, bioassay, and
enzyme-linked immunosorbent assay (ELISA). The effect of viral exposure
on testosterone production by Leydig cells was also investigated.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(1–2 x
108 U/mg) and recombinant rat IFN (4 x
106 U/mg) were obtained from Innogenetics (Ghent, Belgium).
Mouse antirat IFN monoclonal antibodies (DB1; 18,000 neutralizing
units/mg) were purchased from Biosource International (Camarillo, CA).
Rabbit antimouse/rat IFN/ß polyclonal antibodies (55,000
neutralizing units/mg) were purchased from Lee Biomolecular (San Diego,
CA), and enzymes were purchased from Sigma (Saint Quentin Fallavier,
France).
Leydig cell and testicular macrophage isolation and culture
Cell suspensions highly enriched for Leydig cells and testicular
macrophages were prepared from adult rat testes according to the
multistep isolation method of Klinefelter et al. (14). This
procedure involves the use of testicular perfusion, enzymatic
dissociation, centrifugal elutriation, and density Percoll gradient
centrifugation. After centrifugation, the Percoll gradient was divided
into a fraction lighter than 1.068 g/ml that contained germ cells,
macrophages, and damaged Leydig cells and a fraction heavier than 1.068
g/ml that contained intact and steroidogenically active Leydig cells.
At this stage, the purity of the Leydig cells was 94% or more, as
assessed by 3ß-hydroxysteroid dehydrogenase staining of the cells.
Contaminants were mainly testicular macrophages (<4%), peritubular
cells (
0.5%), and very few Sertoli and germ cells. Testicular
macrophages were plated for 15 min in medium supplemented with 10%
FCS, followed by five extensive washing cycles with PBS to remove
contaminating cells. The degree of purity of testicular macrophages was
94% or more, as verified using both the ED2 antibody (Serotec, Oxford,
UK) that reacts with a membrane antigen on resident rat macrophages and
the macrophages with phagocytic ability. Testicular macrophage
preparations were slightly contaminated by Leydig cells (1%) and
peritubular cells (0.1%). Rat Leydig cells and testicular macrophages
were cultured for 24 h in Ham’s F-12-DMEM (1:1, vol/vol; Life
Technologies, Cergy Pontoise, France) supplemented with gentamicin (50
µg/ml; Life Technologies), 0.1% BSA (Biosepra, Villeneuve la
Garenne, France), and 10% FCS (Costar, Brumath, France). After 1 day
of culture, the cells were used for RNA extraction, and supernatants
were stored at -80 C until required for further investigation.
Isolation and culture of spermatogonia
Testes of 9-day-old Sprague-Dawley rats were excised and
decapsulated. Seminiferous epithelial cells were enzyme dispersed and
separated by the method previously described by Bellvé et
al. (15), with the modifications introduced by Dym et
al. (16). Briefly, the decapsulated testes were resuspended in PBS
containing collagenase (1.5 mg/ml) and deoxyribonuclease (1 µg/ml)
and incubated at 32 C for 15 min in a shaker operating at 100
cycles/min. After two washes in PBS, small fragments of seminiferous
tubules, mostly devoid of interstitial cells, were incubated in PBS
containing collagenase (1.5 mg/ml), hyaluronidase (1.5 mg/ml), trypsin
(0.5 mg/ml), and deoxyribonuclease (1 µg/ml) for 25 min and incubated
using the conditions described above. The dispersed cells were washed
three times with PBS and successively filtered through 80- and 40-µm
pore size nylon mesh. Cells from the dissociated seminiferous tubules
were then separated by velocity sedimentation at unit gravity at 4 C
using a 2–4% BSA gradient in Ham’s F-12-DMEM. The cells were bottom
loaded into an SP-120 chamber in 30 ml Ham’s F-12-DMEM containing
0.5% BSA, and a gradient was immediately generated using 275 ml each
of 2% and 4% BSA-supplemented media. The cells were allowed to
sediment for a standard period of 2.5 h, and 35 fractions of 15 ml
were then collected. Cell fractions 16–21 corresponding to a 2.8–3%
range of BSA were pooled and centrifuged at 100 x g
for 10 min. They were then resuspended in Ham’s F-12-DMEM and
incubated at 2.5 x 106/ml in Ham’s F-12-DMEM for
2–3 h at 32 C in a humidified atmosphere of 5% CO2-95%
air to eliminate the contaminating somatic myoid and Sertoli cells. The
enriched population of spermatogonial cells (purity, >90%, using
morphological criteria) was then collected and incubated in Ham’s
F-12-DMEM for 15 h in the presence or absence of Sendai virus (100
and 500 Hemaglutinant Unit/ml).
Total RNA preparation
Total RNA was extracted from small quantities of cells with the
kit Perfect RNA (microscale) from Tebu (Le Perray en Yvelines, France).
This kit uses a guanidine isothiocyanate solution for lysis of the
cells and rapid inactivation of the ribonucleases. Total RNA in the
lysate was subsequently bound to a RNA binding matrix, thoroughly
washed to remove contaminants, and then eluted with water. RNA was
quantitated by absorbance at 260 nm with the usual conversion factor of
1 U at 260 nm equivalent to 40 µg/ml.
IFN bioassay
The antiviral bioactivity of IFNs was measured with a standard
microcytopathic inhibition assay derived from the method of Rubinstein
et al. (17), using rat C6 glial cells (provided
by Prof. Poindron, Strasbourg, France) and vesicular stomatitis virus
(VSV) as the challenge virus. Samples were applied in serial 2-fold
dilutions on the C6 glial cells (5 x 105
cells/well of 96-well plates). Each sample was run in duplicate and
assayed at least three times in three independent assays. In each
series of determination, eight wells per plate served as cell controls,
and eight wells per plate served as virus controls. As there is no
available international standard for rat IFNs, standard laboratory
preparations of rat recombinant IFN (1–2 x 108
U/mg) (18) and rat recombinant IFN (4 x 106 U/mg)
(19) as well as supernatants of macrophages stimulated with Sendai
virus were also titrated on the plates. Samples, standards, and
controls were incubated for 18 h at 37 C. Then, the cultures were
washed and challenged with 5000 plaque-forming units virus/well for
18 h at 37 C. The cytopathic effect observed microscopically was
compared with that in virus control wells, which showed a 90–100%
cytopathic effect. The reciprocal of the highest dilution of the sample
causing 50% protection was taken as the IFN titer. One unit of the IFN
thus defined was equivalent to 10 reference units of rat IFN and to
1 reference unit of rat IFN. Using this method, the sensitivity of
the bioassay was 100 pg/ml for recombinant rat IFN and 400 pg/ml for
recombinant rat IFN. The data are expressed as the mean ±
SEM of groups consisting of three independent samples with
the same conditions of stimulation assayed three times in three
independent assays. Results are expressed as IFN (arbitrary) units per
106 cells.
IFN characterization
Neutralization of antiviral activity by rabbit antimouse/rat
IFN/ß antibodies (55,000 neutralizing units/mg) and mouse antirat
IFN antibodies (18,000 neutralizing units/mg) were measured by the
microcytopathic inhibition method. Before assay, samples were incubated
at 37 C for 4 h with either antibody or control IgG. IFN/ß
antibodies were used at a concentration of 2750 neutralizing units/ml
(dilution, 1:20) and IFN antibodies at a concentration of 1,800
neutralizing units/ml (dilution, 1:20). Controls with rabbit and mouse
IgG were performed at the same time and at the same dilutions. The
efficacy and specificity of the antibodies were pretested on
recombinant rat IFN and -. The possible effect of antibodies on
C6 glial cells was also tested by incubating the cells for 4 h at
37 C with each antibody.
IFN ELISA
Samples were tested for their IFN content using a rat IFN
ELISA kit previously described by van der Meide and colleagues (20)
that was purchased from Biosource International. The rat IFN assay
is a solid phase ELISA. Samples and standards were incubated in
microtiter wells coated with a monoclonal antibody specific for rat
IFN. During this incubation period, rat IFN is bound to the solid
phase. Unbound material present in the samples was removed by washing.
A preformed detector complex consisting of a biotinylated second
monoclonal antibody to rat IFN and a streptavidin-alkaline
phosphatase conjugate was then added to the wells. When rat IFN was
present in the sample, the detector complex bound to the solid phase.
After further incubation, the excess detector complex was removed by
washing, and a para-nitrophenyl phosphate substrate solution
was added to the wells. Color developed proportionally to the amount of
IFN present in the sample. The absorbance at 405 nm was measured.
The assay has a minimum detection level of 12.5 pg/ml.
RT-PCR
To analyze the expression of IFN1 and IFN in the different
cell preparations, RT-PCR was performed on total RNA as follows. The
first strand complementary DNA (cDNA) synthesis was accomplished, as
recommended by Promega (Madison, WI), starting from 10 µg RNA
template with 20 µg/ml hexanucleotides, and 200 U Moloney murine
leukemia virus reverse transcriptase in the reaction medium
Tris-HCl-MgCl2 containing 0.5 mM of each
deoxy-NTP, 10 mM dithiothreitol, and 40 U RNasin in a final
volume of 20 µl. After incubation for 1 h at 37 C, the reaction
volume was brought up to 200 µl. A negative control was performed at
the same time, using the same reaction mixture without Moloney murine
leukemia virus reverse transcriptase, to ensure the absence of any
trace of contaminating genomic DNA in the RNA template.
RT-PCR was carried out as recommended by Perkin-Elmer (Norwalk, CT), starting with 250 ng total RNAs, performing the RT and using the resulting cDNAs as template. Amplification took place for 30 cycles (1 min at 94 C, 1 min at 54 or 60 C, and 2 min at 72 C) in a trio-thermoblock thermocycler (Biometra, Gottingen, Germany).
Negative controls (RNAs before RT) and positive controls (lymphocyte
cDNAs and cDNAs from Sendai virus-exposed macrophages) for IFN and
IFN, respectively, were analyzed for each RT-PCR. The IFN gene
has no intron; thus, RNA samples without reverse transcriptase were run
with each IFN RT-PCR to ensure that there was no genomic DNA
contamination in the samples used. Oligonucleotide primers were chosen
according to the sequence data deposited in GenBank (assession no.
M89641 for IFN and M29315 and M29316 for IFN) and synthesized by
Genset (Paris, France). The sequences of primers used for RT-PCR were:
for IFN1: 5'-primer: 391CCT CAG CCT CTT CAC ATC
AA410; and 3'-primer, 715TGT GGC TCA GGA CTC
ATT TC696; for IFN: 5'-primer, 160ATC TGG
AGG AAC TGG CAA AAG GAC G184; and 3'-primer,
447CCT TAG GCT AGA TTC TGG TGA CAG C423.
RT-PCR was used to amplify a 288-bp fragment specific to the IFN
nucleic sequence and a 325-bp sequence corresponding to the IFN1
retro-transcribed messenger. RT-PCR products were electrophoresed in a
1.5% agarose gel with 0.5 mg/ml ethidium bromide and visualized under
UV light. These RT-PCR products were validated by direct sequencing
using an automated DNA sequencer (373 A, Applied Biosystems, Foster
City, CA).
Testosterone assay
Testosterone levels were assayed using a specific RIA kit
purchased from Medgenix (Rungis, France). This assay is based on the
competition of a fixed amount of 125I-labeled testosterone
with the testosterone to be measured in the samples or the standard,
for antibody sites immobilized on the wall of polystyrene tubes. After
a 3-h incubation at 37 C, an aspiration step terminated the competition
reaction. The tubes were then washed, the count of bound label was
measured, and a standard curve was plotted. The testosterone
concentrations of the samples were determined by comparison with the
standard curve.
Statistical analyses
Results are expressed as the mean ± SEM.
Statistical analysis was performed using two-tailed Student’s
t test. P < 0.05 is defined as
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
Spermatogonia, in the presence of Sendai virus, produced very low
amounts of IFNs, in contrast to virus-exposed Leydig cells and
macrophages, which exhibited extremely high antiviral activity.
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/ß and IFN;
thus, it was necessary to identify the IFN responsible for the
antiviral activity using IFN-specific antibodies. Under the
experimental conditions described here, we show that 2750 neutralizing
units/ml antimouse IFN/ß antibody neutralized about 60% of the
antiviral activity of 500 U/ml recombinant IFN, whereas 1800
neutralizing units/ml IFN antibody neutralized 97% of the antiviral
activity of 312 U/ml recombinant IFN (Fig. 2A). Rabbit IgG (control for rabbit
antimouse/rat IFN/ß antibody) and mouse IgG (control for mouse
antirat IFN antibody) were run in similar concentrations and did not
exert any effect on the IFN activities detected (data not shown).
Figure 2B shows that the antimouse/rat IFN/ß antibody neutralized
about 90% of the activity produced in media from testicular macrophage
and Leydig cell cultures and 100% of the activity in media from
spermatogonia exposed to Sendai virus. It was also found that anti-IFN
antibody only partially reduced (25%) the antiviral activity
observed in media from Leydig cells stimulated by Sendai virus, whereas
the combination of anti-IFN and anti-IFN antibodies inhibited
virtually all the antiviral activity of media from Leydig cell
cultures. Therefore, the reduction of VSV cytopathogen effects observed
for macrophages and spermatogonia probably results from IFN/ß
action, whereas the antiviral activity exerted by Leydig cells reflects
the actions of both IFN/ß and IFN.
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1 in the rat and other species,
IFN1 is generally the most prominently represented (4, 19). We
therefore looked for the presence of IFN1 messenger RNA (mRNA) in
testicular macrophages, Leydig cells, and spermatogonia exposed (or
not) to Sendai virus, using RT-PCR analysis. For each sample, negative
controls (RNA without reverse transcriptase) were performed, and Sendai
virus-infected peritoneal macrophages (100 HAU/ml) were used as a
positive control. The expected 325-bp DNA fragment seen in the
peritoneal macrophages (Fig. 3, A–C) was
also present in Leydig cells, testicular macrophages and spermatogonia
regardless of whether the virus was present. The 325-bp PCR product was
sequenced and found to be identical to the IFN1-coding sequence
(data not shown).
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ELISA protein was assayed in the media of cultures of
testicular macrophages, Leydig cells, and spermatogonia, using an
ELISA. In three independent experiments, very low concentrations of
IFN were detected in media of culture of Leydig cells without Sendai
virus. These concentrations were markedly increased in a dose-dependent
manner when Leydig cells were cultured with 100 or 500 HAU/ml virus
(Fig. 4). In contrast, neither testicular
macrophages nor spermatogonia, with or without Sendai virus, were found
to produce IFN (data not shown).
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).
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was performed on preparations from the
different testicular cell types exposed (or not) to the Sendai virus to
further establish IFN expression. Rat spleen cDNA was run as a
positive control. PCR products corresponding to IFN mRNA were found
in spleen cells and Leydig cells cultured with Sendai virus (high
IFN response) or without virus (low response). No response was
observed in testicular macrophages or spermatogonia regardless of
whether they were incubated with Sendai virus (Fig. 6). A 100% identity was found between
the 288-bp PCR product obtained and the IFN-coding sequence (data
not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß are produced by peritubular and Sertoli cells when
exposed to virus in vitro. In contrast, we have shown that
pachytene spermatocytes and early spermatids are not or are only
marginally influenced by Sendai virus and that early spermatids appear
to be the only tubular cell type producing IFN.
The previous study (5) did not consider spermatogonia, which are not
isolated from the interstitial compartment by the Sertoli cell tight
junctions as the meiotic and postmeiotic germ cells are (1, 2, 28, 29).
The basal location of these germ line precursors can therefore expose
them directly to virus infection. This could lead to dramatic effects,
including destruction of the germ line or diffusion of the virus or
viral DNA into the germ cells. Such spermatogonial contamination has
been described in the cases of HIV (22) and hepatitis B virus (23), and
HIV has also been found in spermatozoa (26), but at present it is not
totally clear whether this contamination occurred within the tubule
itself or during the transit of spermatozoa through the epididymis and
the deferent duct. Despite the high potential risk of infection of
spermatogonia, our results show that these cells did not constitutively
express biologically active IFNs, that they hardly responded to
exposure to Sendai virus, and that they were totally devoid of IFN
expression. However, using the very sensitive RT-PCR technique, we
detected very low levels of IFN1 mRNA in spermatogonia. It could be
argued that the somatic contaminants (mainly peritubular cells) present
in this germ cell fraction are responsible for this IFN1 expression
or that spermatogonial IFN1 is not translated into protein or is
present at low levels that are undetectable in our bioassay. Although
this may be true for Sendai virus, we cannot exclude the possibility
that some other, as yet unidentified, virus could trigger IFN
production by spermatogonia. However, it seems likely that antiviral
protection of spermatogonia is essentially constituted by the somatic
peritubular and Sertoli cells (5). As spermatogonia have access to the
products of the interstitial compartment, they may also benefit from
the protection of interstitial cells, as both testicular macrophages
and Leydig cells are important producers of IFNs.
Of all the testicular cell types tested, Leydig cells present the
strongest antiviral potential. As a result of their interstitial
location, Leydig cells can act as a first line of defense to viruses
coming from the circulation by producing IFNs to protect both
themselves and their neighbors. Not only do Leydig cells produce
extremely high levels of type I IFNs after viral exposure [twice as
much per cell as macrophages and Sertoli cells (5)], but they are the
only testicular cells that produce both type I and type II IFNs.
Therefore, it appears that Leydig cells possess antiviral potential, as
yet another fundamental function in their support of spermatogenesis
and control of secondary sexual characteristics. We have shown that
Leydig cell IFN and testosterone production is increased when these
cells are cultured in the presence of Sendai virus for a short period
(15 h). Thus, it could be that enhanced IFN and testosterone production
is the basic response of Leydig cells to an acute viral attack. This
hypothesis requires demonstration in vivo. Decreased
testosteronemia is often encountered in men suffering from acquired
immunodeficiency syndrome (30, 31), before wasting (32), but it is not
clear whether this results from an alteration of the
hypothalamo-pituitary system or from primary testicular failure (33).
It is interesting to note in this context that testosterone
administration is now used in the treatment of human immunodeficiency
virus-associated wasting (34). In addition to their own potential
antiviral capability, Leydig cells may be supported by neighboring
macrophages, which also appear to be strong producers of type I
IFNs.
Previous studies have demonstrated the influence of IFN on Leydig
cell steroidogenesis in vitro. Orava (35) described a
dose-dependent inhibitory effect of porcine IFN on hCG-stimulated
testosterone production by porcine Leydig cells in culture, and Meikle
et al. (36) also found an inhibitory effect of recombinant
murine IFN on testosterone production by LH-stimulated murine Leydig
cells. Similarly, an inhibition of basal testosterone production was
observed by Orava (35) at high concentrations of IFN (20 ng/ml).
In the present study we observed a stimulation of testosterone levels
after viral exposure concurrent with the production of low
concentrations of IFN in the medium (46–130 pg/ml); thus, we
conclude that it is most likely that the effect of Sendai virus on
Leydig cells is direct, as IFN either has no effect at low
concentration or inhibits testosterone production. The nature of the
mechanism(s) involved in this direct viral action remains to be
elucidated.
Together with our previous study performed on seminiferous tubule cells (5), we establish here the precise topography of IFN expression within the testis. This allows us to hypothesize that for a virus coming from the blood, the first line of defense in the testis is ensured by Leydig cells and testicular macrophages, and the second line is peritubular and Sertoli cells.
In addition to their antiviral properties, IFN have been shown to exert
antiproliferative and immunoregulatory effects (4). The testis is a
major site of cell division and is immunologically privileged. The
demonstration that some testicular cells are able to produce relatively
high concentrations of type I IFNs and IFN dictate further avenues
of research in these important aspects of testicular physiology.
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Acknowledgments |
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and IFN, to Dr. A. Ruffault (Rennes, France) for the kind
gift of Sendai virus and VSV, and to Drs. M. Samson and D. Dresser for
valuable advice. |
Footnotes |
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Received December 5, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and - expression in the rat
testis. Endocrinology 136:4925–4931[Abstract]
. Nucleic Acids Res 119:453–474
in biological
fluids. J Interferon Res 10:183–189[Medline]
and - on testosterone production in porcine
Leydig cell culture. J Interferon Res 9:135–141[Medline]
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