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Messenger Ribonucleic Acid in Rat Sertoli Cells Is Dependent upon Interaction with Germ Cells1
Department of Woman and Child Health (C.K.J., M.H., O.S.), Astrid Lindgren Children’s Hospital, Pediatric Endocrinology Unit, Karolinska Hospital Q2:08, SE-17176 Stockholm, Sweden; Department of Neuroscience (R.H.Z.), Karolinska Institute, SE-17177 Stockholm, Sweden; and Department of Anatomy (M.P.), University of Turku, FIN-20520 Turku, Finland
Address all correspondence and requests for reprints to: Cecilia Jonsson, M.D., Department of Woman and Child Health, Astrid Lindgren Children’s Hospital, Pediatric Endocrinology Unit, Karolinska Institute & Hospital Q2:08, SE-17176 Stockholm, Sweden. E-mail cecilia.jonsson{at}kbh.ki.se
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Abstract |
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and IL-1ß, of which IL-1ß is the major
inducible IL-1 protein produced by macrophages. We show here that mRNA
of IL-1, but not IL-1ß, is constitutively expressed by the intact
rat testis and localize the transcript to Sertoli cells as confirmed by
a novel squash technique. The expression is developmentally regulated
and appears only after postnatal day 20 in the rat testis,
corresponding to onset of puberty. IL-1 mRNA shows a stage-dependent
expression pattern during the cycle of the seminiferous epithelium. It
is low or absent in stage VII, but present in all other stages of the
cycle. The same stage-dependent distribution was also observed at the
protein level when bioactive IL-1 was measured in extracts of
accurately defined one millimeter segments of seminiferous tubules. No
IL-1 mRNA was detected in adult rat testes after germ cell depletion
by fetal irradiation or cytostatic drug treatment. Because stage VII is
the only segment of the seminiferous tubules lacking DNA replication,
we propose that IL-1 is involved in this event during mitosis and
meiosis of spermatogenesis and that its expression is dependent upon
interactions between Sertoli cells and germ cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(IL-1), a cytokine
originally detected as a rapidly inducible proinflammatory mediator of
activated mononuclear phagocytes (1), has also been found to be
constitutively produced by certain intact tissues in the absence of
local inflammation (2), indicating noninflammatory paracrine
function(s) at these sites. Of such tissues, the adult testis and
stratified squamous epithelium of the skin and some mucous membranes
have been found to produce abundant amounts of IL-1 (for review, see
Ref. 3) On the other hand, IL-1ß, which is the predominant (more than
90%) proinflammatory IL-1 isoform secreted by activated mononuclear
phagocytes (4), does not seem to display a similar constitutive
production pattern as IL-1.
In the rat testis, bioactive IL-1 protein first appears during puberty
and in the adult rat the production remains constantly high, although
displaying a stage-dependent production (5, 6). The function of
testicular IL-1 is obscure, but some data indicate that it may be
involved in the paracrine regulation of germ cell growth and
differentiation during spermatogenesis (7, 8).
The cellular origin of testicular IL-1 has been debated. We
and others have proposed that Sertoli cells are the main source
under constitutive conditions (6, 9), whereas other authors have
suggested that it is produced by germ cells (10). In this study, we
have used in situ hybridization histochemistry to localize
IL-1 mRNA in normal rat testes of different ages and also in adult
rat testes after experimental depletion of germ cells, using fetal
irradiation or cytostatic drug treatment. Our results demonstrate that
IL-1, but not IL-1ß or IL-6 mRNA, is constitutively expressed
under noninflammatory conditions by Sertoli cells in the intact adult
rat testis. The expression seems to be dependent upon interaction with
germ cells.
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Materials and Methods |
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Preparation of activated rat macrophages
Peritoneal exudate cells were obtained from two 60-day-old rats
by peritoneal lavage with -modified Eagle’s MEM containing
penicillin (100 U/ml), streptomycin (100 µg/ml) (-MEM), and
heparin (100 U/ml) 2 days after ip injection of 3 ml of Freund’s
Complete Adjuvant (Difco, Kebo Laboratories, Stockholm) and paraffin
oil (1:1, v:v) to induce aseptic peritonitis. The obtained cells were
used as a crude source of activated rat macrophages. The lavage fluid
was collected in 50 ml tubes and the cells were pelleted by
centrifugation, reconstituted in -MEM, pooled and pelleted again in
Eppendorf tubes, and then immediately frozen at -70 C.
RNA was extracted from the cell pellet as described below.
Preparation of polyadenylated RNA and complementary DNA (cDNA)
Total RNA was extracted from rat testis (n = 3) by
Ultraspec Total RNA Isolation Kit (Biotecx Laboratories, Houston, TX)
according to the manufacturer’s protocol. Polyadenylated RNA
(poly(A)RNA) was isolated from total RNA using Hybond mAP
(Amersham Pharmacia Biotech Sweden AB, Solna, Sweden),
i.e. poly(U) filters as described by the manufacturer. The
isolated poly(A)RNA was dissolved in distilled water, precipitated with
ethanol, and stored at -20 C. The isolated poly(A)RNA was further
processed, using Superscript cDNA kit (Life Technologies, Inc., Gaithersburg, MD) to synthesize cDNA. The oligonucleotide 5'-CTC CTT
CAG CAA CAC AGG–3', complementary to positions 688–671 in the
published rat IL-1 cDNA sequence (12) (Innovagen, Lund, Sweden) was
used as a primer for Maloney murine leukemia virus RNase
H-reverse transcriptase (Life Technologies, Inc.) to obtain rat IL-1 cDNA. One µg of poly(A)RNA was
treated with 400 U of the enzyme in a reaction volume of 20 µl, and
incubated for 2 h at 45 C in the presence of 60 U of RNase
Inhibitor (Promega Corp., Madison, WI). The reaction was
stopped by freezing the sample at -20 C. The end product was used
directly for PCR. Rat IL-1ß and IL-6 cDNA was synthesized from
oligonucleotide primers as previously described (13).
PCR analysis of IL-1, IL-1ß, and IL-6 cDNA
For IL-1, two 21-nucleotide primers were synthesized using
the rat IL-1 sequence published by Nishida et al. (1989)
as a template. The upstream primer (5'-GAC CAT CTG TCT CTG AAT CAG-3')
correspond to positions 136–157 in the published sequence and the
downstream primer (5'-CGA TGA GTA GGC ATA CAT GTC-3') was complementary
to bases at positions 589–569. The primers were deliberately chosen so
that they would encompass several exons to avoid confusion with any
amplified genomic IL-1 DNA. PCR primer pairs for rat IL-1ß and
IL-6 were designed as described previously (13). PCR was performed on a
Perkin-Elmer Cetus DNA Thermal Cycler 480 in a reaction
volume of 50 µl in the presence of 0.5 µM primers, 0.2
mM dNTP, 2 mM MgCl2 and 1.5 U of
AmpliTaq DNA polymerase (Perkin-Elmer Cetus, Norwalk, CT).
The steps in the PCR reaction included time delay (94 C for 5 min),
step-cycle (96 C for 1 min, 53 C for 30 sec and 72 C for 3 min),
altogether 35 cycles, after that a 5-min time delay at 72 C, and
finally a soak file at 4 C for at least 5 min. Aliquots (10 µl) of
all samples were separated on a 2% agarose gel containing ethidium
bromide (15 µg to 100 ml of agarose gel). The gel was run for
1.5 h at 75 V and photographed under UV light.
Preparation of oligonucleotide probes
A unique oligonucleotide probe complementary to nucleotides
264–313 in rat IL-1 mRNA (12) without similarities to known
sequences (GenBank, NIH) were synthesized (Scandinavian Gene Synthesis
AB, Köping, Sweden). The probe was radiolabeled with
[35S] deoxyadenosine 5'-[-thio]triphosphate (NEN) at
the 3' end using terminal deoxynucleotidyl transferase (Amersham Pharmacia Biotech, Stockholm, Sweden). Specificity controls
included: 1) Use of a second probe complementary to another part of the
rat IL-1 mRNA strand (nucleotides 365–414). The patterns observed
with the two complementary probes were identical. Use of the two probes
together intensified the hybridization signal. 2) Use of a 50-bp random
probe, with similar length and GC content. No localized or specific
hybridization was found with this probe. 3) Liver was used as a
positive control, demonstrating IL-1 expression in Kupffer
cells.
In situ hybridization
ISHH was performed according to Dagerlind et al.
(14). In brief, sections were hybridized for 16–18 h at 42 C in
humidified boxes and rinsed 5 x 15 min in 1 x SSC at 60 C.
Tissue sections were then dehydrated, air-dried, dipped in photographic
emulsion (NTB-2, Kodak, Stockholm, Sweden) diluted 1:1 in
deionized water, exposed for 6 weeks at 4 C, developed for 4 min (D-19,
Kodak), fixed for 6 min (mixture of 3000A & B,
Kodak) and rinsed 30 min under running water before being
counterstained with cresyl-violet and mounted (Entellan, Merck & Co., Inc., Stockholm, Sweden). Sections were examined using
bright- and dark-field and phase contrast microscopy (Axiophot,
Carl Zeiss, Stockholm, Sweden and Nikon,
Eclipse, E800, Bergström Instrument, Solna, Sweden).
Microdissection of seminiferous tubules
In the rat, the epithelial cycle of the seminiferous tubules can
be divided into 14 different cell associations also called stages. The
stages can be identified based upon the variations in light absorption
in a transillumination stereomicroscope (15). A long piece of a single
seminiferous tubule containing one complete wave of the seminiferous
epithelium was microdissected sequentially by taking intermittent
control segments (0.5 mm) and 1 mm segments. The 0.5 mm segments were
squashed under a coverslip, and the cells were identified by
morphological criteria by phase contrast microscopy (16). From the 1 mm
segments, proteins was extracted by homogenizing the piece of tissue in
50 µl of -modification of Eagle’s MEM (-MEM). To determine the
levels of IL-1, the homogenates were centrifuged and 10 µl
duplicate samples of the supernatants from the segments were analyzed
in the IL-1 bioassay as described below.
Bioassay of IL-1
IL-1 bioactivity of extracts of the tubular segments was
determined by a murine thymocyte proliferation assay (11). Thymocytes
(3.5–5 x 106 cells/ml) from 4- to 6-week-old highly
IL-1 responsive NMRI-KI mice were cultured with samples in the presence
of phytohemaglutinin (PHA, 5 µg/ml) in 96-well microtiter plates. The
plates were incubated at 37 C and harvested at 48 h following a
2-h pulse of tritiated thymidine (0.5 µCi/well). The thymocyte
proliferation, as assessed by the incorporation of radioactivity and
measured in cpm, was used as an estimation of IL-1 bioactivity. Culture
medium (-MEM) was used as negative control and aqueous tissue
extracts of whole adult rat testes (2) as a positive control.
Bioassay of IL-6
Bioactive IL-6 protein was assayed using 7TDI hybridoma
cells as described previously. Mouse recombinant IL-6 and rat tissue
(injured brain) were used as positive controls (13).
Postnatal germ cell depletion by busulfan treatment
Busulfan dissolved in a mixture of dimethylsulphoxide:water
(1:1), was injected ip in 60-day-old male rats. A single dose of
busulfan of 10 mg/kg bw resulted in a transient germ cell depletion
(17). Higher doses of busulfan were tested but were avoided due to
increased mortality of the rats. The testes were analyzed 60 (n =
2) and 120 (n = 3) days after busulfan treatment.
Prenatal germ cell depletion by fetal irradiation
Pregnant rats were irradiated with 1.5 Gy as a single dose
(60Co 
emitter, 1.03 min, focal length: 77 cm) at day 19
of gestation. This treatment has been reported to create a complete and
irreversible loss of germ cells in the male offspring (18, 19). Testes
were taken out and processed for in situ hybridization 100
days postnatally (n = 5).
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Results |
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but not
IL-1ß or IL-6 mRNA in intact 60-day-old rat testes. In contrast, all
three transcripts of expected size (IL-1 453 bp, IL-1ß 545 bp, and
IL-6 488 bp), respectively were present in RNA isolated from activated
rat macrophages used as a positive control (Fig. 1
). No attempts were made to quantify the
testicular IL-1 PCR product. Bioactive IL-1 protein but not IL-6 was
found in aqueous extracts of intact adult rat testes (data not
shown).
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but not IL-1ß or IL-6 could be detected
by PCR in the intact rat testis, all further studies focused on
IL-1. In situ hybridization histochemistry using rat
IL-1 specific probes revealed distinct expression of IL-1 mRNA in
the rat testis. The expression patterns in testes of 55- and
100-day-old rats were identical, indicating that the IL-1 expression
remains qualitatively unchanged during adult life (Fig. 2, A and B, 55-day-old rat). The IL-1
transcripts were detected only in seminiferous tubules and were
localized specifically to the peripheral parts. The adluminal portion
of the seminiferous tubules as well as the interstitial tissue showed
no obvious IL-1 mRNA labeling over background. Moreover, we could
not detect any IL-1 expression in testes from 10-day-old rats. Even
in testes from 20-day-old rats, the IL-1 transcript was undetectable
by in situ hybridization (Fig. 2, C and D). Sections
hybridized to the random probe did not display any localized signal
(Fig. 2E shows 55-day-old testis), whereas positive control tissue (rat
liver) showed the expected mRNA expression in Kuppfer cells (Fig. 2F).
A strictly stage-dependent expression pattern was found in the adult
testes. All stages except for stage VII, which was negative, showed
expression of IL-1 mRNA in the periphery of the seminiferous tubules
(Fig. 3, A and B). Bioactive IL-1 protein
extracted from microdissected consecutive accurately defined segments
of seminiferous tubules showed the same stage-dependent distribution as
IL-1 mRNA. Thus, stage VII displayed low, if any, IL-1 bioactivity
whereas all other stages showed clearly detectable levels (Fig. 3C).
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mRNA were Sertoli cells
according to localization (Fig. 4A),
though we could not exclude a weak expression in premeiotic germ cells.
Further support for this view came from experiments where we have used
the squash preparation technique to more accurately discriminate
between different cell types. In squash preparations from testes of
adult rats (55 days) we found a distinct expression of IL-1 mRNA
localized to Sertoli cells (Fig. 4B), identified by their apparent
nucleoli and attached spermatid bundles. In testes from busulfan
treated rats, we found a distinct IL-1 mRNA expression pattern in
seminiferous tubules that had recovered from the treatment (120 days
after busulfan, Fig. 5A). In tubules that
had not recovered from busulfan treatment (60 days after busulfan, Fig. 5B), we could not detect any localized IL-1 mRNA expression. Testes
from animals that were prenatally exposed to irradiation had a
Sertoli-cell-only morphology and did never establish spermatogenesis.
In these testes, lacking developing germ cells, no clear IL-1 mRNA
signal was detected by in situ hybridization (Fig. 5, C and
D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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but not IL-1ß or IL-6 mRNA
is constitutively expressed by Sertoli cells in testes of intact adult
rats. The expression of IL-1 mRNA was found to be stage dependent
and present in all stages except for stage VII, which also showed low
production of bioactive IL-1 protein. The IL-1 mRNA was localized to
the periphery of the seminiferous tubules in tissue sections. A Sertoli
cell origin of the IL-1 transcripts was indicated from dark field
and phase contrast microscopy of squash preparations of microdissected
seminiferous tubule segments, allowing accurate identification of
single labeled cells by morphological appearance and typical cellular
interconnections. All intensely labeled cells were identified as
Sertoli cells, but the methods used cannot totally exclude a low
expression level of IL-1 mRNA also in a few premeiotic germ cells.
There is no evidence of constitutive IL-1 expression in haploid germ
cells, interstitial cells, or in peritubular cells. The IL-1 mRNA
expression was found to be dependent upon interaction with germ cells.
Thus, testes devoid of active spermatogenesis lacked distinct
expression signal, whereas the IL-1 signal reappeared after restart
of spermatogenesis. This observation is in line with the changes
previously observed for bioactive IL-1 protein during repopulation of
seminiferous epithelium after transient germ cell depletion by local
irradiation of testes of adult rats (20). A stage dependency of IL-1
protein has previously also been demonstrated in pooled preparations of
staged seminiferous tubule segments (5). We were able to strengthen
these previous findings by determination of bioactive IL-1 protein
in 1 mm consecutive microdissected segments of single seminiferous
tubules with precise stage identification by morphological analysis of
squashed intermittent control segments. The obtained results were in
total agreement with the observed stage dependency of the IL-1 mRNA
expression. Regulation of Sertoli cell function by interaction with germ cells has also been demonstrated in other models. Thus, androgen binding protein (21), plasminogen activator (22), and FSH-dependent cAMP production (23) by Sertoli cells have previously been shown to be affected by germ cells or germ cell products.
Our findings on the constitutive cellular distribution of IL-1 mRNA
in intact adult rat testes in vivo accord with those made by
Gérard and co-workers (9), demonstrating production of IL-1
protein by cultured Sertoli cells.
Our present results, however, contrast to those of Haugen et
al. (10), who demonstrated IL-1 protein and mRNA in cellular
extracts of isolated postmeiotic germ cells but not of Sertoli cells.
Further, in this study we have failed to demonstrate any constitutive
expression of IL-6 mRNA and protein by the intact adult rat testis
in vivo, which is in conflict with the findings of Hakovirta
et al. (24) and Syed et al. (25), who showed
expression of IL-6 in the rat testis in vitro. However,
demonstration of proinflammatory cytokines such as IL-1, IL-1 receptor
antagonist, IL-6 or tumor necrosis factor- by sensitive techniques
after cell or tissue manipulation in vitro must be
interpreted with much caution as these immunoinflammatory messengers
are rapidly induced by a variety of unspecific stimuli. It may well
be that the referred discrepancies are due to induction of the
respective cytokine by the in vitro culture conditions used
in the cited studies (10, 24, 25). Our present in vivo
findings of a constitutive expression of IL-1 in Sertoli cells
indicate a potential role of this cytokine in normal adult testis
physiology, whereas the inducible expression of IL-1 and IL-6 may
reflect important pathophysiological activation pathways in the testis.
The putative physiological role of IL-1 is strengthen by our finding
that the tissue concentration of IL-1 protein in the adult testis
under constitutive conditions is approximately 1 pM
(Söder, O., unpublished observations).
Recent evidence from IL-1 receptor type I gene knock-out mice has
failed to demonstrate any effect on testis function (26). The type I
IL-1 receptor is, in contrast to the type II receptor, the only
signaling IL-1 receptor, and it binds IL-1 and IL-1ß with equal
affinity (for review, see Ref. 27). This latter observation, in
combination with studies showing the same biological effects of
purified biosynthetic IL-1 and IL-1ß, have formed the concept
that the two IL-1 agonists are functionally identical. However,
IL-1 and IL-1ß show surprisingly low primary structure
homology (28), and there are a number of examples revealing
differential effects of IL-1 and IL-1ß (28, 29, 30, 31). In the rat
testis, we have found that IL-1ß, but not IL-1, exerts
proinflammatory activity after local injection (32) and a similar
discrepancy between IL-1 and IL-1ß action has been found with
respect to the effects on Leydig cell function in vitro
(33).
IL-1 has been shown to act as a growth factor for a variety of
different cell types (34, 35), including germ cells as shown by our own
studies (7, 8). An indirect support of such a growth factor function
was provided by the present finding of a negligible expression of
IL-1 in stage VII of the seminiferous epithelial cycle, as this
stage has a very low (or absent) number of proliferating germ cells (7, 8). We conclude that the present results favor a physiological role of
IL-1 as a germ cell growth factor in the testis. The exact mechanism
of action and the receptors involved are still to be elucidated.
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Acknowledgments |
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Footnotes |
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Received August 14, 1998.
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References |
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. Endocrinology 129:1614–1620 stimulation of spermatogonial proliferation
in vivo. Reprod Fertil Dev 1:85–87[CrossRef][Medline]
synthesis in rat testis. Mol Cell Endocrinol 82:R13–R16
cDNA. J Biochem 105:351–357, in conscious, freely-moving rats. Biochem Biophys
Res Commun 146:1286–1290[CrossRef][Medline]
, induces inflammation-like changes in the
testicular microcirculation of adult rats. J Reprod Immunol 17:155–165[CrossRef][Medline]
acts as an autocrine
growth stimulator for human gastric carcinoma cells. Cancer Res 53:4102–4106This article has been cited by other articles:
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