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Biology of Reproduction 59, 1419-1424 (1998)
©Copyright 1998 Society for the Study of Reproduction, Inc.

Expression of Interleukin-1 System Genes in Human Gametes1

Maria José de los Santosa,c, Deborah J. Andersona, Catherine Racowskyb, Carlos Simónc, and Joseph A. Hill2,a,b

a Fearing Research Laboratory and b the Center for Reproductive Medicine, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215 c Instituto Valenciano de Infertilidad, Valencia, Spain


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
There is considerable evidence that the interleukin-1 (IL-1) system plays an important role in ovarian and testicular physiology, implantation, and other reproductive events. Human embryos express IL-1ß, IL-1 receptor type I (IL-1RtI), and IL-1 receptor antagonist (IL-1RA) at both the mRNA and protein levels. The presence of IL-1{alpha} and IL-1ß in oocyte-conditioned media and on the surface of human oocytes suggests that these cells may also produce this cytokine; however, whether the IL-1 system gene products are present as stable mRNAs in human gametes (oocytes and spermatozoa) has not yet been demonstrated.

We used stringent cell separation techniques combined with reverse transcription-polymerase chain reaction to investigate the expression of various IL-1 system genes (IL-1{alpha}, IL-1ß, IL-1RtI, and IL-1RA) in human gametes and cumulus cells. Our results indicate that freshly isolated cumulus cells express all these IL-1 system components. On the other hand, IL-1{alpha}, IL-1ß, and IL-1RtI mRNAs were not found in either unfertilized or fertilized human oocytes, and a very few metaphase II human oocytes had transcripts for either secreted (10%) or intracellular (17%) IL-1RA. Mature spermatozoa did not contain mRNA for any of the of the IL-1 system components. The absence of informational RNA for the IL-1 system components in human unfertilized and polyploid oocytes and fresh immature oocytes suggests that maternal transcripts for these genes do not contribute to early embryo development. The presence of IL-1 components at the protein level in human oocytes may be due to binding of IL-1 produced by cumulus cells or other cell types, or to prior intrafollicle transcription and translation. Likewise, IL-1 system components do not appear to have a physiological role in mature spermatozoa since none of these components are present at the mRNA or protein levels, and important functional parameters such as motility and acrosome reaction appear not to be affected by IL-1ß in vitro. However, the abundant expression of IL-1{alpha}, IL-1ß, the IL-1RtI, and its antagonist IL-1RA by human cumulus cells provides further evidence that the IL-1 system plays a role in human ovarian physiology.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Interleukin-1 (IL-1) was first identified as a macrophage-derived lymphocyte activating factor [1]. It is now known as a gene system with pleiotropic effects that extend beyond the immune system. The ligand has two forms, IL-1{alpha} and IL-1ß, that can be produced by a variety of cells. Two different receptors, IL-1RtI and IL-1RtII, are present constitutively in many different target cells [2]. Soluble IL-1 receptor (sIL-1R) and IL-1RtII, together with a natural IL-1 antagonist (IL-1RA), regulate IL-1 biologic activity [3, 4].

IL-1 has been shown to play a role in reproduction. In the ovary, IL-1 has been reported to have an intermediary role during the periovulatory events and corpus luteum formation in different mammalian species. For example, in rats, IL-1ß stimulates the expression of important components of the ovulatory cascade such as metalloproteinases [5] and ovarian prostaglandin [6]. The ability of IL-1ß to induce ovulation in cultures of rat preovulatory follicles [7] and rabbit perfused ovaries has also been demonstrated [8]. IL-1{alpha} and IL-1ß have also been shown to inhibit progesterone synthesis in basal and hCG-stimulated human granulosa cells cocultured with white blood cells [9].

An increasing number of reports also have documented the presence of the IL-1 system components in testicular tissue [10, 11] as well as effects of IL-1 on testicular function in vitro. IL-1 has been shown to affect both germ cell and immature Leydig cell proliferation [12, 13], and to modulate adult Leydig and Sertoli cell function [14, 15]. These experimental models support the concept that IL-1 plays a role in the autocrine and paracrine regulation of normal and pathophysiological testicular function.

High concentrations of IL-1ß may also interfere with reproductive processes. One study has shown that IL-1ß at 5–20 IU/ml impaired fertilization in the hamster ova sperm penetration assay (SPA) and mouse zona binding assay [16]; however, another study did not find any effect even at a higher concentration of IL-1 [17]. High concentrations of IL-1 reportedly inhibit mouse embryo development in vitro [18].

The presence of IL-1{alpha} and IL-1ß in conditioned media from human oocyte cultures [19–22] suggests that these cells may be capable of secreting IL-1. However, oocyte-conditioned media are normally collected 16–18 h after oocyte insemination [19, 21], and they usually contain other cell types such as cumulus cells and semen cells that potentially could produce IL-1.

Transcriptional arrest is a phenomenon that occurs in both mature spermatozoa and oocytes. Human fetal oocytes in the early diplotene stage [23] and immature preovulatory human oocytes from nonstimulated ovaries [24] present an active [3H]uridine incorporation profile indicating active RNA transcription. This large number of mRNAs is stored for long periods of time before their use after fertilization [25]. During testicular germ cell maturation, chromatin changes lead to the total loss of nucleosomes and the cessation of transcription during mid-spermiogenesis [26]. Therefore, the presence of stable mRNAs is one of the mechanisms for supplying essential proteins once transcription is arrested. These stable mRNAs are translated at specific times toward the end of gametogenesis [25, 26]. It is unknown whether transcripts of the components of the IL-1 system are present as stable pools of RNAs in human spermatozoa and/or oocytes.

The objective of our study was to combine stringent cell separation techniques with the ultrasensitive reverse-transcription-polymerase chain reaction (RT-PCR) methodology to determine whether human gametes (unfertilized oocytes, polyploid oocytes, and spermatozoa) and cumulus cells have detectable IL-1 system gene product components. Such information may provide further evidence for a role of the IL-1 system in gamete physiology and early embryonic development.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Human Gametes

After informed consent was obtained, 108 human oocytes, including fresh immature oocytes (1 prophase I and 3 metaphase I) and oocytes from failed or abnormal fertilization attempts (6 prophase I, 29 metaphase I, 53 metaphase II, 12 polyploid, and 4 vacuolated or fragmented), were analyzed from women participating in the Assisted Reproductive Technology program within the Center for Reproductive Medicine at the Brigham and Women's Hospital, Boston, MA.

Semen samples were collected from 5 healthy donors by masturbation into sterile containers. Semen was liquefied at room temperature for 30 min. After centrifugation at 500 x g for 30 min at room temperature, semen cells were fractionated on discontinuous Percoll gradients (Pharmacia LKB Nuclear Inc., Gaithersburg, MD) consisting of 90%, 70%, and 45% layers. Cells harvested from interfaces—which we designated a (0–45%), b (45–70%), c (70–90%), and d (pellet) d—were washed once with Ham's F-10 with HEPES (Gibco BRL Life Technologies, Grand Island, NY). An aliquot from each interface was stained using the Papanicolau technique and carefully evaluated for the presence of round cells to ensure the purity of sperm in the Percoll pellet.

RNA Extraction from Human Gametes

Twenty-four-hour-old oocytes were washed carefully in Ham's F-10 HEPES-buffered media and placed in Tyrode's Salt Solution, pH 2.1 (both from Gibco BRL Life Technologies) for no more than 20 sec to remove the zona pellucida and the remaining attached corona-cumulus cells. Once it was confirmed that all oocytes were free of cumulus cell contamination, they were stored at -80°C in 19 µl of RT mixture (see below) containing 0.5% Nonidet P-40.

The seminal cell fractions were dissolved in a 6 M guanidinium thiocyanate solution (Gibco BRL Life Technologies) consisting of 0.5% sodium lauryl sarcosinate and 0.1% mercaptoethanol (Sigma Chemical Co., St. Louis, MO). The lysates were layered onto a cushion of CsCl, 0.001 M EDTA (pH 7.5) and centrifuged at 15°C for 26 h at 94 000 x g. The recovered RNA was mixed with 3 M sodium acetate and 100% ice-cold ethanol and was stored overnight to precipitate at -20°C. The RNA was pelleted and washed with 70% ethanol and then dissolved in 8 µl of RNase, DNase-free water. The concentration of RNA was calculated by spectrophotometry at 260 nm [27].

RT-PCR

Total RNA from semen cell fractions, cumulus cells, single oocytes, and 100 cells from the 1/E6E7 endocervical cell line [28] was dissolved in 20 µl of buffer consisting of 5.2 mM MgCl2, 10.5 mM Tris-HCl, 52.6 mM KCl, 20 U of RNase inhibitor, 0.05 nmol of random hexamers, 50 U of Molony murine leukemia virus reverse transcriptase (MuLV; Perkin Elmer, Branchburg, NJ), and 5.2 nmol each of nucleotide mixture (dNTP). The RNA was reverse-transcribed for 10 min at 22°C and 42 min at 42°C, and then incubated for 5 min at 95°C to inactivate the MuLV.

Complementary DNA from cumulus cells, oocytes, sperm fractions, and 100 control cells (1/E6E7 endocervical line) was used as a template for PCR amplification of the IL-1 system components by means of Amplitaq Gold polymerase (Perkin Elmer) in a reaction mixture of 30 µl containing 1.67 mM MgCl2, 10 mM Tris-HCl, 50 mM KCl, and 200 µM digoxigenin (DIG)-labeled nucleotide mix (Boehringer Mannheim, Indianapolis, IN). The 42-cycle profile consisted of denaturation at 95°C for 15 sec, annealing at 50–60°C for 30 sec, and extension at 72°C for 30 sec. To verify the success of cDNA synthesis, cDNA from oocytes was analyzed by PCR using primers for histidyl tRNA synthetase (HistRs), whereas for seminal cell fractions, ß-actin primers were used. Additionally, PCR for CD45 and c-kit mRNA were used to detect, respectively, white blood cell contamination and the presence of immature germinal cells. The amplified products were visualized on 1% and 3% agarose gels, depending on the product size, after staining with ethidium bromide, which revealed the expected fragment size under ultraviolet light. Their identities were confirmed using PCR-ELISA and/or heminested PCR. Primers were chosen to span introns, thereby allowing discrimination between PCR products derived from cDNA templates and from genomic DNA templates. The primers [29–32] and probes are listed in Figure 1.



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  		FIG. 1. Primers and probes used for RT-PCR. A, upstream primer; B, inner downstream primer; C, outer downstream primer. PE and CLP primer sequences were provided by Perkin Elmer and Continental Laboratory Products, Inc., respectively. The inner downstream primers and probes were designed with the help of the Biomolecular Research Tools program, Internet address: http://www.public.iastate.edu/~pedro/rt_1.html

PCR-ELISA Detection

The PCR-ELISA detection assay was performed in duplicate as described in the manufacturer's manual (Boehringer Mannheim) with slight modifications. In brief, 5 µl of the PCR product was denatured with 20 µl of denaturation buffer. After 5–10 min, the single DNA strains were hybridized with specific biotin-labeled probes (Fig. 1) and incubated for 3 h at 55°C in avidin-coated wells. Each well was washed three times and then incubated for 30 min in the presence of 200 µl (10 mU/ml) of anti-DIG peroxidase-conjugated antibody; and after another three washes, the wells were incubated with 200 µl of ABTS substrate (2,2'-azinobis[3-ethylbenzothiazoline-6-sulfonic acid]) for 20–30 min. Absorbance was measured in an ELISA reader plate at 405 nm (reference filter 492 nm).

Heminested PCR

Heminested PCR was performed using 0.6 µl of the amplified product as a template for the second PCR amplification, and using the same PCR conditions but an inner downstream primer and unlabeled nucleotides (Fig. 1).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Detection of IL-1 System Transcripts in Cumulus Cells and Oocytes

Complementary DNA synthesis was successful since the amplification product for HistRs was detected in all samples from individual oocytes as well as in cumulus cell and in endocervical 1/E6E7 cell cDNA preparations. No product was detected in the oocyte culture supernatant extracted and subjected to RT-PCR, which was used as a negative control (Fig. 2B). One sixth of the total cDNA from individual oocytes and one sixth of the cDNA from 100 cells of the endocervical 1/E6E7 cell line (approximately 17 cell equivalents) were used for each PCR to amplify each component of the IL-1 system plus the HistRs. After the first round of PCR, the samples were tested either by the PCR/ELISA assay, which also detected a very low level of amplification normally undetectable by the conventional ethidium bromide-stained agarose gels, or by heminested PCR. Heminested PCR was also used to amplify the PCR products of oocytes so that the correct molecular mass could be confirmed in agarose gels. For a few oocytes (n = 10), half of the cDNA was analyzed for all the IL-1 system components with identical results. The sensitivity of the primers was 1-cell equivalents of the control 1/E6E7 endocervical cell line for IL-1{alpha}, 2-cell equivalents for IL-1ß, and 17-cell equivalents for IL-1RtI, sIL-RA, and intracellular (ic) IL-1RA (data not shown). RT-PCR analysis of RNA from the positive control endocervical 1/E6E7 cell line showed expression of all the IL-1 system components studied (Fig. 2A).



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  		FIG. 2. A) Agarose gel showing the PCR products of the IL-1 system from semen cells from Percoll fractions (a, 0-45%, b, 45-70%; c, 70-90%; d, pellet), oocytes (O), and cumulus cells (CC). Amplifications of sIL1RA and icIL-1RA from oocyte RNA were detectable only by ELISA/PCR assay. In order to show the products for sIL-1RA and icIL-RA in oocytes, bands from the heminested protocol are included in this figure. Control experiments using 17 cell equivalents of endocervical cell line 1/E6E7 (E) indicated satisfactory amplification of all components of the IL-1 system. Oocyte medium supernatant was used as a negative control (c-). B) RT-PCR for HistRs showed successful cDNA synthesis in O, CC, and E. Notice that Percoll fractions c and d, containing pure spermatozoa, were positive for ß-actin mRNA, but did not show transcriptional activity for any of the components of the IL-1 system. C) Heminested PCR for IL-1{alpha}, IL-1ß, and IL-1RtI of the positive samples showing a smaller size after the use of their respective inner downstream primers.

To rule out false positive results due to leukocyte contamination, PCR for CD45 was performed (Fig. 2B). The majority of the cumulus cell RNA preparations tested negative for CD45. CD45-negative cumulus cells expressed IL-1{alpha}, IL-1ß, and IL-1RtI. We also detected transcription for both the soluble and intracellular forms of the IL-1 system natural antagonist (sIL-1RA and icIL-1RA, respectively) in these samples (Fig. 2A).

None of the 108 oocytes analyzed were positive for IL-1{alpha}, IL-ß, or IL-1RtI. Five of 98 oocytes (5%) contained transcripts for sIL-1RA, and 9 of 108 oocytes (8%) were positive for icIL-1RA. All positive oocytes for both sIL-1RA and icIL-1RA were metaphase II; therefore, the percentage of positive metaphase II oocytes was 10% (5 of 51) for sIL-1RA and 17% (9 of 53) for icIL-1RA.

IL-1 System Expression in Cells from Human Semen

All semen samples contained spermatozoa, white blood cells, and immature germ cells. ß-Actin amplification was positive in all cell fractions, including mature spermatozoa (Fig. 2B). Microscopic examination and the absence of CD45 mRNA in both Percoll interface c and pellet d confirmed the purity of our spermatozoa population after Percoll separation. The vast majority of round cells remained between the a and b Percoll interfaces, where CD45 mRNA expression was also positive (Fig. 2B). None of the samples examined contained detectable levels of transcripts for c-kit, which is a positive control for testicular germ cells.

Results from PCR amplification of the IL-1 system components in pure spermatozoa and round cell-containing fractions are also shown in Figure 2A. Pure spermatozoa from fractions c and d did not express any of the IL-1 system components. IL-1ß and sIL-1RA mRNAs were found in Percoll gradient interfaces a and b. IL-1RtI mRNA was detected in interface a only. IL-1{alpha} mRNA was not found in any of the four Percoll fractions.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In our study, we used random hexamers to optimize the generation of cDNA combined with the most sensitive PCR approaches available. Using this strategy, individual oocytes were positive for HistRs RNA. However, neither IL-1{alpha}, IL-1ß, nor IL-1RtI transcripts were detected in unfertilized or polyploid human oocytes, and only very few, all of them MII oocytes, expressed IL-1RA. This is in contrast to observations made with unfertilized mouse oocytes, which contain IL-1 mRNA transcripts [33]. Thus, our data suggest a species-specific difference in expression of IL-1 transcripts in unfertilized oocytes.

It is possible that mRNA for components of the IL-1 system, except IL-1RA, belongs to the second class of transcripts described by Reppolee et al. [34], which only appears as a result of zygotic transcription, as occurs for insulin-like growth factor (IGF)-I, IGF-II, IL-6, and leukemia inhibitory factor [28, 35–37]. Alternatively, either degradation of maternal mRNA after failed fertilization, or poly (A) RNA decrease during meiotic maturation, as occurs in mice [38], could explain this negative result. To test the latter possibility, four fresh immature oocytes (1 prophase I and 3 metaphase I) were included in this study; these oocytes also did not express any of the IL-1 system components. This suggests absence of these gene products on full-grown immature human oocytes.

The regulation of mRNA decay may be one of the mechanisms used to establish steady-state message levels of particular gene products including certain cytokines [39]. IL-1{alpha} and IL-1ß mRNAs have AU-rich sequence elements involved in selective shortening of mRNA half-life. Interestingly IL-1RA does not contain this sequence. This may explain our inability to detect transcripts for IL-1{alpha} and IL-1ß whereas IL-1RA was detected in a few oocytes. The presence of IL-1 system components at the protein level in unfertilized oocytes, as described previously [40], may be due to intrafollicle transcription and translation during oogenesis or, alternatively, to binding to oocytes of IL-1 produced by other cell types. Transcripts for IL-1ß, IL-1RtI, and IL-1RA that have been described in blastomeres from 8- to 12-cell human embryos [41] imply zygotic transcription for the main components of the IL-1 system.

Cumulus cells are known to express IL-1ß and IL-RtI [42]. We also detected IL-1{alpha} and the soluble and intracellular forms of IL-1RA. To our knowledge, ours is the first study reporting that fresh isolated cumulus cells express icIL-1RA and sIL-1RA. The expression of the intracellular version of IL-1RA may function as a protective mechanism for cells exposed to inflammatory stimuli, as icIL-1RA expressed in the epithelial surface of the ovary has been reported to attenuate IL-1 responses at a point downstream of the initial IL-1/IL-1RtI interaction [43]. Furthermore, it has been shown that cAMP is a second messenger for IL-1 [44], and that high concentrations of intracellular cAMP inhibit oocyte maturation [45]. Therefore, secretion of IL-1RA by cumulus cells could neutralize inhibitory effects of IL-1 on oocyte maturation and thus facilitate fertilization and further embryo development. Interestingly, ovulated rabbit oocytes triggered by IL-1 in perfused ovaries have significantly lower fertilization rates than ovulated oocytes triggered by hCG [8]. Our data also suggest that cumulus cells attached to the zona pellucida may be the source of IL-1 reported in oocyte and embryo cultures in vitro, since even after mechanical disruption, cumulus cells may still remain attached to oocytes and embryos. In our study, all oocytes were confirmed to be free of cumulus cell contamination by careful microscopic evaluation.

IL-1{alpha}, IL-1ß, and IL-1RA have been detected in seminal plasma from normo-, oligo-, astheno-, and azoospermic men [46–48]. White blood cells present in seminal plasma of these men may be the source of the IL-1 system products in these samples [46]. However, other cells from the reproductive tract may also be capable of IL-1 secretion, such as Sertoli, Leydig, and epithelial cells [10, 49, 50]. IL-1 system gene expression was undetectable in pure mature human spermatozoa recovered from Percoll gradient interfaces c and d. These results support previous observations that conditioned media from pure sperm cells are devoid of IL-1-like activity [19]. Moreover, whereas IL-1 is mitogenic for rat testicular germ cells, suggesting the presence of IL-1 receptor in these cells, IL-1 has no effect on human sperm motion parameters [51] and on spontaneous and ionophore-induced acrosome reactions [52]. Results are also conflicting on whether IL-1 affects sperm fertilization ability in the SPA assay [16, 17]. IL-1RtI and IL-1RtII mRNA was detected in murine testicular germ cells, but not in human pachytene spermatocytes and early spermatids [11]. Thus, none of the IL-1 system gene products that we investigated appear to be represented among the stable mRNAs that can persist in the sperm head or in the sperm-associated cytoplasmic droplets of the mature spermatozoa.

In summary, the absence of informational RNA encoding IL-1 system components in human unfertilized oocytes, polyploid oocytes, and fresh immature oocytes provides evidence that maternal mRNAs for such proteins are not required before embryonic transcription begins at the zygotic stage. Furthermore, the IL-1 system does not appear to have a physiological role in mature spermatozoa since none of these components are detectable at protein (unpublished observations) or mRNA levels. However, expression of IL-1 system components by human cumulus cells provides further evidence that the IL-1 system plays a role in human ovarian physiology.


   ACKNOWLEDGMENTS
 
We thank Aida Nuredin, David Travassos, Glen Adaniya, Kathy Jackson, Shehua Shen, Jennifer Kelly, and Caroline Balint from the In Vitro Fertilization Laboratory at the Brigham and Women's Hospital for their help during the oocyte collection.


   FOOTNOTES
 
1 This work was supported in part by grants AI38515 and HD33276 from the National Institute of Health, Bethesda, MD; by the Fearing Research Laboratory Endowment; and by the Instituto Valenciano de Infertilidad. Back

2 Correspondence: Joseph A. Hill, Reproductive Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. FAX: 617 566 7752; jahill{at}bics.bwh.harvard.edu Back

Accepted: July 30, 1998.

Received: April 2, 1998.


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 DISCUSSION
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