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Endocrinology Vol. 141, No. 11 4114-4119
Copyright © 2000 by The Endocrine Society

ARTICLES

Expression of Tumor Necrosis Factor-Stimulated Gene-6 in the Rat Ovary in Response to an Ovulatory Dose of Gonadotropin1

Shinya Yoshioka, Scott Ochsner, Darryl L. Russell, Takeshi Ujioka, Shingo Fujii, Joanne S. Richards and Lawrence L. Espey

Department of Biology (S.Y., T.U., L.L.E.), Trinity University, San Antonio, Texas 78212; Department of Cell Biology (S.O., D.L.R., J.S.R.), Baylor College of Medicine, Houston, Texas 77030; and Department of Gynecology and Obstetrics (S.F.), Kyoto University School of Medicine, Kyoto 606, Japan

Address all correspondence and requests for reprints to: Lawrence Espey, Ph.D., Department of Biology, Trinity University, San Antonio, Texas 78212. E-mail: lespey{at}trinity.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Current evidence supports the hypothesis that the biochemical events of mammalian ovulation are analogous to an acute inflammatory reaction. This study reveals that tumor necrosis factor-stimulated gene-6 (TSG-6), which encodes a member of the superfamily of hyaluronan-binding proteins that is specifically translated in inflammatory reactions, is expressed in ovarian follicles that have been induced to ovulate. Immature Wistar rats were primed with 10 IU equine CG sc; and 48 h later, the 12-h ovulatory process was initiated by 10 IU human CG (hCG), sc. Ovarian RNA was extracted at 0, 2, 4, 8, 12, and 24 h after the primed animals were injected with hCG. The RNA extracts were used for RT-PCR differential display of amplified complementary DNAs (cDNAs) that represented gene expression in the stimulated ovarian tissue. Northern analysis of one of the differentially amplified cDNAs confirmed that it was part of a gene that was substantially up-regulated at 4–8 h after the ovaries had been stimulated by hCG. Subcloning and sequence analysis revealed that the cDNA matched the gene for TSG-6. In situ hybridization indicated that the TSG-6 messenger RNA was primarily located in the cumulus mass and the antral granulosa cells of large ovarian follicles. In conclusion, the data show that expression of TSG-6 is an integral part of the cascade of inflammatory-like changes that occur in an ovulatory follicle in response to a trophic hormone that couples with luteinizing hormone/hCG receptors.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
FOR THE PAST 2 decades, mammalian ovulation has been characterized as an acute inflammatory reaction that is induced in mature ovarian follicles by a surge in pituitary gonadotropin(s) (1, 2, 3). The proinflammatory cytokines interleukin (IL)-1 and tumor necrosis factor-{alpha} (TNF-{alpha}), which are primary mediators of the acute phase response (4), have both been firmly implicated in the ovulatory process (5, 6, 7). These two cytokines activate a number of inflammation-related genes, including TNF-stimulated gene-6 (TSG-6), which is reportedly translated only in inflammatory reactions (4, 8). The present report describes the detection by RT-PCR differential display of TSG-6 gene expression in rat ovarian follicles that had been induced to ovulate by treatment with gonadotropin.

TSG-6 is a so-called link protein that binds rather specifically to hyaluronan (HA) (4), a glycosaminoglycan that has a central role in the formation and stability of extracellular matrix (9, 10). Interestingly, when HA and TSG-6 exist independently of one another, HA reportedly has a proinflammatory effect, whereas the TSG-6 protein exerts an opposite effect (11). Nevertheless, in spite of its potent antiinflammatory properties, TSG-6 expression is considered to be an integral part of inflammatory processes [presumably affecting the early stages of an acute inflammatory response (4, 11)].

The distribution of HA in ovarian follicles has been studied extensively (10, 12). This glycosaminoglycan is thought to have an especially significant role in the expansion of the cumulus cell-oocyte complex (COC) shortly after the ovulatory process has been initiated by a surge in gonadotropin(s). Such hormone action induces a transient, but detectable, increase in the synthesis of HA by mural granulosa cells, along with a substantial increase in HA production by the cumulus granulosa cells (13, 14). In the latter instance, the accompanying expansion of the COC is thought to be important for ovulation and fertilization (12).

It has been reported recently that TSG-6 is also expressed in the COC of mice at approximately the same time as the ovulatory increase in HA synthesis (9, 15). In the present study, this member of the link module superfamily was discovered by PAGE display of RT-PCR products of messenger RNA (mRNA) extracts from rat ovaries. The results from in situ hybridization show that ovarian expression of TSG-6 mRNA extends beyond the cumulus oophorus and includes the mural granulosa. In addition, the report analyzes the temporal pattern of expression of this link-protein gene, and it assesses the affect of ovulation-inhibiting doses of indomethacin and epostane on ovarian expression of the gene.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animal tissue and animal injections
Immature Wistar rats were induced to superovulate by equine CG and human CG (hCG) treatment, as described previously (16). Ovarian RNA was extracted at the periovulatory intervals of 0, 2, 4, 8, 12, and 24 h after hCG. These nucleic acid extracts were used for differential display and for Northern blotting. Epostane (courtesy of Sanofi Pharmaceuticals, Inc.-Synthelabo Research, Malvern, PA) and indomethacin (Sigma, St. Louis, MO) were injected sc, also as described previously (16). These antiovulatory agents were administered, at 3 h after hCG, in doses of 5.0 mg and 1.0 mg, respectively. The ovulation rate in the various experimental animals was determined by a procedure that also has been described previously (16). For the determination of ovulation rate and the extraction of ovarian RNA, rats were killed by exposure to CO2. The animals were acquired, retained, and used in compliance with the NIH Guide and with the approval of the institutional animal care review committee.

Differential display protocols that lead to detection of TSG-6
The steps of the differential display were carried out as described previously (16). In brief, RNA was extracted by a standard guanidine isothiocyanate/cesium chloride procedure. RT- PCR was performed using primers from an RNAimage Kit (G506, GenHunter Corporation, Nashville, TN). The specific primer set that yielded differentially expressed complementary DNA (cDNA) for TSG-6 was 5'-HTTTTTTTTTC-3' and 5'-HGGCTGAC-3', where H represents a HindIII restriction site attached to the primers. After extraction and reamplification of the differentially expressed cDNA, a standard Northern analysis was performed to confirm the ovulation-specific expression of the parent mRNA for TSG-6. The unique cDNA fragment was cloned using a pCR-TRAP Cloning System (P404, GenHunter Corporation), and a cloning colony containing the TSG-6 cDNA was identified by secondary Northern analysis. Manual sequencing of the cDNA was performed using a Sequenase Version 2.0 DNA Sequencing Kit (US70770, Amersham Pharmacia Biotech, Piscataway, NJ). In situ hybridization was performed as described previously (16).

Statistical analysis
Densitometric analysis of the intensity of the signals from the Northern blots was analyzed by the NIH-image program, as described previously (16). Numerical data are presented as means ± SEM. The significance of the differences among the six principal time points of 0, 2, 4, 8, 12, and 24 h after hCG was determined by Duncan’s multiple-range tests after a completely randomized one-way ANOVA of the means of the groups. The probability value used as the cutoff between significant and not-significant levels was P = 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Differential display of TSG-6 cDNA during the ovulatory process
After RT-PCR, the subpopulations of radioactively labeled cDNAs that were generated from RNA extracts at each of the six stages of the periovulatory period were separated from one another by electrophoresis on a polyacrylamide gel. The autoradiograph of these PAGE results revealed differentially expressed cDNA bands that were only moderately conspicuous, with strongest amplification in the lanes containing PCR products from mRNA that was extracted at 4 and 8 h after hCG (Fig. 1Go). Therefore, the most intense cDNA band (i.e. the band in the 8-h lane) was excised from the acrylamide gel and reamplified for use as a probe in Northern analysis.



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  		Figure 1. Autoradiograph of differentially displayed TSG-6 cDNA (arrow). Note that the cDNA is not visible in the 0–2 h RT-PCR product, and the greatest amplification is at 4–8 h.

 
Northern analysis of TSG-6 mRNA expression during ovulation
The Northerns revealed a pattern of mRNA expression during ovulation that was similar to the pattern on the differential display autoradiograph (Fig. 2Go). The strongest signals on the Northerns were from hybridization with mRNA that had been extracted at 4 and 8 h after hCG. By a discretionary precedent in our laboratory, the intensity of the signal from the 8-h lane was arbitrarily set at 100%, and the densities at the other points during the periovulatory period were expressed as fractions of that maximum. Accordingly, the NIH-image program was used to digitize all of the bands on the Northerns, and the ratio of the density of each experimental band to its corresponding ß-actin control band was calculated for each lane. Based on five Northern blots, the signal densities at 0, 2, 4, 8, 12, and 24 h after hCG were 0%, 17.0 ± 6.7%, 113.2 ± 33.3%, 100%, 22.7 ± 2.9%, and 8.9 ± 1.3%, respectively. Thus, TSG-6 gene expression was at a maximum at 4–8 h into the ovulatory process, and this expression declined significantly before the follicles began rupturing at 12–14 h after hCG.



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  		Figure 2. Amount of ovarian TSG-6 mRNA, as determined by intensity of Northern blot signals at six intervals of the periovulatory period after hCG administration. Solid dots represent the mean value of three Northern blots prepared from two separate RNA extractions from two batches of rats. The signal density at 8 h was arbitrarily set at 100%. An actual Northern analysis of the TSG-6 cDNA and its ß-actin control are shown below the graph. Note that the pattern of signal intensity is comparable with the RT-PCR amplification shown in Fig. 1Go. a, Significantly different from 0-h control.

 
Sequence of the cDNA fragment for TSG-6
After the ovulation-specific expression of the TSG-6 gene had been confirmed by Northern analysis, the cDNA fragment of this gene was cloned and sequenced. The length of the sequence between the primers was 233 bp. The National Center for Biotechnology Information (NCBI) accession number for this fragment is AF159103. The cDNA fragment is highly homologous to a segment of a gene (NCBI accession no. U83903) that has been cloned recently from hCG-stimulated murine COC tissue (15). Also, the TSG-6 gene fragment is homologous with a gene (NCBI accession no. M86381) that is expressed after serum stimulation of quiescent vascular smooth muscle cells from the rabbit (17). Likewise, the fragment is homologous with a gene (NCBI accession no. M31165) that is expressed by TNF-treated human FS-4 fibroblasts (18).

Effects of epostane and indomethacin on TSG-6 gene expression
For these tests, Northern blots were prepared from RNA that was extracted from control ovaries at 0 and 8 h into the ovulatory process, or extracted from experimental ovaries that were taken at 8 h after hCG from rats that had been treated 5 h earlier with ovulation-inhibiting doses of epostane or indomethacin (19). As in the Northern blotting tests at the six different intervals during ovulation, the signal density (normalized against the ß-actin control) of the 8-h lane was arbitrarily set at 100% (Fig. 3Go). There was no detectable expression of TSG-6 mRNA at 0 h, but substantial expression at 8 h. In animals treated with the antiovulatory agent epostane, which blocks progesterone synthesis, the signal density of 74.1 ± 6.3% was not significantly different from the 8-h control value. However, animals treated with the antiovulatory agent indomethacin, which blocks prostanoid synthesis, had a TSG-6 mRNA level of 49.5 ± 11.8%, which was significantly below the 8 h control value, yet above the 0 h control value.



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  		Figure 3. Comparison of the TSG-6 mRNA signal, from Northern blots, with data on ovulation rate in parallel groups of animals that were treated with either 5 mg epostane (Epo) or 1 mg indomethacin (Indo), administered at 3 h after hCG. Ovarian RNA was extracted at 8 h after hCG treatment because this was near the peak level and because the data could be compared with the pattern of expression of other ovulation-related genes (16 27 ). The bar graphs that quantitate Northern blot data are based on NIH Image analyses of three different Northern blots that were prepared from one RNA extraction from experimental groups consisting of seven rats each, i.e. the RNA extracts were pooled from seven pairs of ovaries. The signal from the 8-h control lane was arbitrarily set at 100% OD to compare the intensities of signals from the four different Northern blots. In parallel groups of rats, the ovulation rate was determined, at the optimal time of 24 h after hCG, by counting ova in the oviducts. a, Significantly different from 0-h control; b, significantly different from the 8- and 24-h controls (Ctrl).

 
Localization of TSG-6 mRNA expression by in situ hybridization
In situ hybridization confirmed the temporal pattern of TSG-6 mRNA expression that was observed in the differential display autoradiograph and the Northern analysis. There was negligible signal at 0–2 h into the ovulatory process, a strong signal at 4–8 h, and only a trace of signal by 12 h after hCG (Fig. 4Go). Hybridization was limited to the granulosa layer (including the cumulus mass) of the follicles, but the intensity of the signal was not distributed evenly. The largest follicles (i.e. the follicles that were sectioned on a plane closest to the maximum diameter of mature follicles) exhibited a more intense signal for TSG-6 mRNA along the innermost granulosa cells located adjacent to the follicular antrum (Fig. 5Go). Intensity of the in situ signal from indomethacin-treated ovaries did not seem different from controls (Fig. 6Go).



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  		Figure 4. Change in intensity of the in situ hybridization signal for TSG-6 mRNA during the six periovulatory intervals after hCG administration. Lightfield micrographs on the left show the histology of ovarian sections stained with hematoxylin and eosin, whereas the darkfield micrographs of the same sections show the localization of TSG-6 mRNA as detected by hybridization of a 35S-labeled antisense probe derived from the TSG-6 cDNA. Magnification, approximately x7.

 


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  		Figure 5. Closer view of the distribution of TSG-6 mRNA probe in the 8-h ovary. Note that the signal is particularly strong in the vicinity of the cumulus mass (white arrow) and the antral granulosa cells. Magnification, approximately x50.

 


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  		Figure 6. Comparison of the intensity of the in situ hybridization signal from the ovaries of indo-treated animals vs. 8-h control tissue. Note that the indo-treated ovary has essentially the same amount of signal as the control tissue. Magnification, approximately x50.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
A decade ago, TSG-6 was first discovered during a search for TNF-activated genes by differential screening of a cDNA library prepared from TNF-treated human FS-4 fibroblasts (20). Since then, it has been recognized that the TSG-6 gene is activated by TNF-{alpha} and IL-1 through a promoter region that includes one AP-1 and two NF-IL6 binding sites (21, 22). Also, the structure of the TSG-6 protein has been characterized in detail (4, 9, 23, 24). TSG-6 is now recognized as a 35-kDa glycoprotein that is one of the shortest members of a superfamily of HA-binding proteins that includes link protein, aggrecan, versican, brevican, neurocan, and CD44, along with TSG-6. The TSG-6 protein is composed of two structural domains: an N-terminal hyaluronin-binding domain consisting of about 100 residues that are characteristic of proteins in the hyaladherin family (4, 9), and a C-terminal CUB domain consisting of about 110 residues that are characteristic of a number of diverse proteins involved in development and differentiation (25, 26). Thus, a basic function of TSG-6 is presumed to be linkage to hyaluronin and stabilization of the extracellular matrix in various tissues during morphogenic processes.

In the present study, ovarian TSG-6 mRNA expression increased to a peak within 4 h after the ovulatory process had been initiated by hCG. It remained elevated for an additional 4 h but then declined, by 12 h after hCG, to a level that was not significantly different from the 0-h control value. This temporal pattern of expression coincides with the increase in IL-1 in rat ovarian follicles in vivo and in vitro (27, 28, 29, 30). In assessing the spatial distribution of TSG-6 mRNA expression, this transcript followed a pattern most comparable with the increase in ovarian HA synthesis after injection of hCG into PMSG-primed mice (13). Not only was TSG-6 expression observed in COC, it was also intense in the mural granulosa cells that were most adjacent to the antrum but was minimal in the outermost layers of the mural granulosa cells.

Expression of ovarian TSG-6 mRNA also coincides with an increase in TNF-{alpha} concentrations in gonadotropin-treated immature rats (31). Therefore, IL-1 and TNF-{alpha} are both candidates as promoters of TSG-6 transcription in ovulatory follicles. At the same time, it is pertinent to take into account that the TNF gene can be regulated by early growth response protein-1 (Egr-1) (32, 33), and expression of the gene for this zinc-finger transcription factor precedes expression of ovarian IL-1, TNF-{alpha}, or TSG-6 during the ovulatory process in the rat model (19). Therefore, it seems likely that Egr-1 has at least an indirect role in the induction of TSG-6 gene expression during ovulation. In the future, it would be useful to conduct a well-controlled, comprehensive study of the temporal and spatial expression of the ovarian genes for Egr-1, IL-1, TNF-{alpha}, and TSG-6 to clarify the relationships among these agents during ovulation. By analyzing such data concomitantly with existing knowledge of the promoter regions of the genes for each agent, their interdependence could be elucidated.

The specific function of TSG-6 in ovulatory follicles has not been established. It seems relevant that the inflammatory cytokines IL-1 and TNF-{alpha} commonly induce transcription of the gene for this member of the link-module superfamily (4, 9). It is also relevant that TSG-6 reportedly is produced only in instances of inflammation (8). This information suggests that TSG-6 has a role in acute inflammatory reactions and participates in extracellular matrix (ECM) degradation associated with inflammatory processes. However, it is not yet clear whether TSG-6 has a destabilizing, or a stabilizing, effect on the ECM during local tissue remodeling that is characteristic of acutely inflamed tissues (9, 11). The preponderance of the evidence unexpectedly supports a stabilizing role for TSG-6. This glycoprotein binds to HA and thereby stabilizes the ECM (4, 9). Furthermore, there is substantial evidence to show that TSG-6 readily forms a stable complex with inter{alpha}-inhibitor (I{alpha}I), a Kunitz-type serine protease inhibitor in the plasma (4). This combination of TSG-6 and I{alpha}I inhibits plasmin, a serine protease that activates matrix metalloproteinases that degrade ECM during inflammatory reactions (4, 11). Thus, the synergistic action of TSG-6 and I{alpha}I has an antiinflammatory effect, which suggests a negative feedback role in moderating acute inflammatory responses.

The hypothesis that TSG-6 binds to HA and interacts with I{alpha}I to protect the COC matrix from degradation is a reasonable deduction (15), because metalloproteinases (such as the inflammation-related enzyme ADAMTS-1) are produced in substantial amounts in the COC and in the stratum granulosum, in response to an ovulatory dose of gonadotropin (34, 35). In any event, there are recent reports that binding of I{alpha}I to HA in the COC is important for optimal ovulation (36, 37). Therefore, TSG-6 could have some pivotal association with these factors that effect stability of the ECM in the vicinity of the oocyte.

In summary, the present results show that ovarian TSG-6 mRNA is expressed chiefly in mural granulosa cells and in cumulus cells around the oocyte. Northern analysis reveals that the mRNA is transcribed relatively early during the ovulatory process, and it declines to nonsignificant levels even before ADAMTS-1 expression has reached its peak at 12 h after hCG (34). Also, the data show that TSG-6 expression is not affected by inhibition of follicular progesterone synthesis, and it is only moderately reduced by inhibition of follicular eicosanoid synthesis. Therefore, TSG-6 probably has a role in ovulation independent of these two well-known mediators of follicular rupture. In any event, the increase in TSG-6 mRNA, in the follicle in response to an ovulatory dose of gonadotropin, provides additional support for the hypothesis that the biochemical events of ovulation are comparable with an acute inflammatory reaction.


   Footnotes
 
1 This work was supported by NSF Grant 9870793 (to L.L.E.); by a grant to support T. Ujioka as a Research Fellow of The Lalor Foundation, Providence, Rhode Island (to L.L.E.); and by NIH Grant HD-16229 (to J.S.R.) Back

Received May 24, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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K. Sayasith, M. Dore, and J. Sirois
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M. Jo, M. C. Gieske, C. E. Payne, S. E. Wheeler-Price, J. B. Gieske, I. V. Ignatius, T. E. Curry Jr., and C. Ko
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M. Shimada, M. Nishibori, Y. Yamashita, J. Ito, T. Mori, and J. S. Richards
Down-Regulated Expression of A Disintegrin and Metalloproteinase with Thrombospondin-Like Repeats-1 by Progesterone Receptor Antagonist Is Associated with Impaired Expansion of Porcine Cumulus-Oocyte Complexes
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T. Fayad, V. Levesque, J. Sirois, D. W. Silversides, and J. G. Lussier
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D. L. Russell, K. M. H. Doyle, S. A. Ochsner, J. D. Sandy, and J. S. Richards
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S. A. Ochsner, A. J. Day, M. S. Rugg, R. M. Breyer, R. H. Gomer, and J. S. Richards
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G. W. Sun, H. Kobayashi, M. Suzuki, N. Kanayama, and T. Terao
Follicle-Stimulating Hormone and Insulin-Like Growth Factor I Synergistically Induce Up-Regulation of Cartilage Link Protein (Crtl1) via Activation of Phosphatidylinositol-Dependent Kinase/Akt in Rat Granulosa Cells
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S. A. Ochsner, D. L. Russell, A. J. Day, R. M. Breyer, and J. S. Richards
Decreased Expression of Tumor Necrosis Factor-{alpha}-Stimulated Gene 6 in Cumulus Cells of the Cyclooxygenase-2 and EP2 Null Mice
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D. L. Russell, S. A. Ochsner, M. Hsieh, S. Mulders, and J. S. Richards
Hormone-Regulated Expression and Localization of Versican in the Rodent Ovary
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L. L. Espey and J. S. Richards
Temporal and Spatial Patterns of Ovarian Gene Transcription Following an Ovulatory Dose of Gonadotropin in the Rat
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S. Varani, J. A. Elvin, C. Yan, J. DeMayo, F. J. DeMayo, H. F. Horton, M. C. Byrne, and M. M. Matzuk
Knockout of Pentraxin 3, a Downstream Target of Growth Differentiation Factor-9, Causes Female Subfertility
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 Recent Prog Horm ResHome page
J. S. Richards, D. L. Russell, S. Ochsner, M. Hsieh, K. H. Doyle, A. E. Falender, Y. K. Lo, and S. C. Sharma
Novel Signaling Pathways That Control Ovarian Follicular Development, Ovulation, and Luteinization
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C. D'Alessandris, R. Canipari, M. Di Giacomo, O. Epifano, A. Camaioni, G. Siracusa, and A. Salustri
Control of Mouse Cumulus Cell-Oocyte Complex Integrity before and after Ovulation: Plasminogen Activator Synthesis and Matrix Degradation
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J. S. Richards
Perspective: The Ovarian Follicle--A Perspective in 2001
Endocrinology, June 1, 2001; 142(6): 2184 - 2193.
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