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Biology of Reproduction 67, 1435-1438 (2002)
© 2002 Society for the Study of Reproduction, Inc.

Regular Article

Testosterone Regulates 25-Hydroxycholesterol Production in Testicular Macrophages1

Yevgeniya Lukyanenkoa, Jau-Jiin Chena, and James C. Hutson2,a

a Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas 79430


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recently, we found that testicular macrophages produce 25-hydroxycholesterol (25-HC) and express 25-hydroxylase, the enzyme that converts cholesterol to 25-HC. In addition, 25-HC may be an important paracrine factor mediating the known interactions between macrophages and neighboring Leydig cells, because it is efficiently converted to testosterone by Leydig cells. The purpose of the present study was to determine if testosterone can regulate the production of 25-HC in rat testicular macrophages, representing a potential negative-feedback loop from Leydig cells. We found that expression of 25-hydroxylase mRNA and production of 25-HC by cultured testicular macrophages were significantly inhibited by testosterone at 10 µg/ml. This dose of testosterone did not have an effect on cell viability and did not change the rate of mRNA degradation in the presence of actinomycin D. These studies indicate that production of 25-HC is negatively regulated by testosterone, which may be representative of a paracrine negative-feedback loop.

interstitial cells, Leydig cells, testis, testosterone


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Testicular macrophages increase in number during postnatal maturation of the testis, keeping a relatively constant macrophage:Leydig cell ratio of 1:3 to 1:4 [1–4]. During this early maturational period, macrophages and Leydig cells form specialized intercellular complexes, suggesting a paracrine interaction between these two diverse cell types [5]. Direct evidence that macrophages influence Leydig cells was provided by experiments demonstrating that culture medium from rat testicular macrophages increases testosterone production by Leydig cells [6, 7]. We have purified the factor responsible for this stimulatory effect and identified it as 25-hydroxycholesterol (25-HC), an oxysterol that is readily converted to testosterone by the cholesterol side-chain cleavage complex within Leydig cells [8, 9]. Additional studies conducted in vivo complemented these early in vitro studies. More specifically, when macrophages were experimentally (in rats) or genetically (in mice) depleted from the testis, testosterone levels fell, indicating that these cells are necessary for normal steroidogenic function [10–14]. Whether 25-HC mediates this phenomenon is not known, but 25-HC has been found in ether extracts of testis, indicating that it is present in vivo and, thereby, that a physiological role for this oxysterol is possible [9]. In addition, 25-HC has been shown to be produced by human macrophages, indicating that it could have clinical importance [15].

For two cells to be truly interactive, each must influence the other. In this regard, we have found that the number of macrophages in the testis increases twofold by 24 h after injecting newborn rat pups with hCG [16, 17]. This suggests that Leydig cells influence the size of the macrophage population, but whether these cells also regulate the amount of 25-HC produced by macrophages is not known. Testicular macrophages express 25-hydroxylase [18], an enzyme that oxidizes cholesterol on carbon 25, producing 25-HC [19, 20]. The goal of the present study was to determine if a negative-feedback mechanism exists whereby testosterone down-regulates the production of 25-HC and the expression of 25-hydroxylase mRNA in testicular macrophages. Viability of testicular macrophages following treatment with testosterone was also studied.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Materials

Male rats (200–400 g, Sprague-Dawley rats; Charles River Laboratories, Inc., Wilmington, MA) were handled in accordance with protocols approved by the Animal Use and Care Committee of Texas Tech University Health Sciences Center (Association for Assessment and Accreditation of Laboratory Animal Care International approved). Dulbecco modified Eagle/F12 medium (DME/F12), testosterone, BSA (fraction V), penicillin, streptomycin, collagenase (type I), placental ribonuclease inhibitor, actinomycin D, and thiazolyl blue (MTT) were obtained from Sigma Chemical Co (St. Louis, MO). The 25-HC (cholest-5-ene-3ß,25-diol) was obtained from Steraloids (Newport, RI). [14C]Cholesterol was from New England Nuclear (Boston, MA). Dishes (diameter, 35 mm) were obtained from Becton Dickinson Labware (Franklin Lakes, NJ). High-performance liquid chromatography (HPLC)-grade organic solvents, avian myleoblastosis virus reverse transcriptase (AMV-RT), and nucleotide mix (dNTPs) were purchased from Fisher Scientific (Fair Lawn, NJ). The HPLC columns (C18, Microsorb MV, 100 angstrom, 4.6 mm x 25 cm) were from Varian Chromatography Systems (Walnut Creek, CA). LightCycler-FastStart DNA Master SYBR Green I reagent kit and glycogen were from Roche Molecular Biochemicals (Indianapolis, IN). Primers for reverse transcriptase-polymerase chain reaction (RT-PCR) were from Midland Certified Reagent Company (Midland, TX). Plasmid containing the 25-hydroxylase cDNA was generously provided by Dr. David W. Russell (University of Texas Southwestern Medical Center, Dallas, TX). Plasmid containing glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was from Ambion (Austin, TX). TRIzol Reagent was from Life Technologies (Grand Island, NY). Mouse Leydig tumor cells (MA-10) were a generous gift from Mario Ascoli (University of Iowa, Iowa City).

Testicular Macrophages

Rats were killed with CO2, and the testes were removed and perfused through the gonadal vein with collagenase (100 U/ml) in medium (DME/F-12 plus 0.1% [w/v] BSA, penicillin [100 U/ml], and streptomycin [100 µg/ml]). The testes were then decapsulated and further digested in collagenase in a shaking water-bath at 120 cycles/min at 37°C. Undigested seminiferous tubules were removed by unit gravity sedimentation and the interstitial cells recovered from the supernatant by centrifugation (350 x g, 6 min). Interstitial cells were suspended in medium and plated into 35-mm culture dishes for 10–15 min to allow rapidly adhering macrophages to attach. Nonadherent cells were then removed by vigorous washing with medium. Cells were maintained in 1 ml of medium at 34°C in a humidified atmosphere of 95% air and 5% CO2 at approximately 200 000 cells/dish. Testicular macrophages isolated in this manner are approximately 95% positive for Fc receptor.

Cell Viability

Following treatment of testicular macrophages with various doses of testosterone (5, 10, 20, and 50 µg/ml) for 24 or 72 h, viability was determined using MTT. The percentage of living cells was determined by counting cells with an inverted phase-contrast microscope where both living (blue) and dead (clear) cells could be identified [21]. Twenty microscopic fields, each representing 62 500 µm2, were sampled for each dish.

Production of 25-HC

After 1–2 h in culture, testicular macrophages were treated for an additional 20–24 h with testosterone (0.1, 1.0, and 10 µg/ml) in 1 ml of medium containing 0.08 µCi [14C]cholesterol in 2 µl of ethanol and 0.2% BSA. The medium was removed, centrifuged at 10 500 x g for 1 min, and twice extracted with three volumes of water-saturated HPLC-grade ether. The organic phase was evaporated to dryness, dissolved in 180 µl of methanol, and chromatographed on a C18 HPLC column using methanol as the mobile phase at 1 ml/min. The amount of [14C]25-HC produced was determined by scintillation spectrometry as previously described [18].

Quantitative Measurement of Steady-State Levels of 25-Hydroxylase mRNA Using "Real-Time" RT-PCR

Testicular macrophages were treated with testosterone (0.5, 1, 5, and 10 µg/ml) in 1 ml of medium. After 24 h, total RNA was isolated using TRIzol reagent plus glycogen (200 µg/ml) according to the manufacturer's recommendations. The cDNAs were then generated using AMV-RT and oligo(dT)12–18 primers at 48°C for 45 min and amplified in a Roche LightCycler using the FastStart DNA Master SYBR Green I reagent kit. Cycle conditions for 25-hydroxylase were: 95°C for 10 min, followed by 40 cycles at 95°C for 15 sec, 58°C for 5 sec, and 72°C for 10 sec. Primer sequences were: 5'-GCGACCCAATACATGAGCTT-3' and 5'-CAAAGGGCACAAGTCTGTGA-3', spanning bases 507–691 of the mouse 25-hydroxylase (GenBank accession no. AF059213). Copy number was determined by comparing the linear portion of the DNA accumulation curves generated by the samples to those curves generated by serially diluted standards (plasmid carrying the 25-hydroxylase cDNA). We have previously sequenced this product and found it to be 25-hydroxylase [18]. No product specific to 25-hydroxylase was observed in the absence of AMV-RT. 25-Hydroxylase transcripts were not found in MA-10 cells and primary cultures of rat Leydig cells, indicating the cellular specificity of 25-hydroxylase expression. Steady-state levels of GAPDH mRNA were also measured. Cycle conditions for GAPDH were: 95°C for 10 min, followed by 40 cycles at 95°C for 15 sec, 50°C for 5 sec, and 72°C for 11 sec. Primer sequences were: 5'-GGGCCAAAAGGGCCATCAT-3' and 5'-ATCACGCCACAGCTTTCCA-3'. The number of 25-hydroxylase transcripts was divided by the number of GAPDH transcripts for each culture dish.

RNA Stability

Testicular macrophages were maintained in culture for 24 h. The cells were then pretreated with actinomycin D (5 µg/ml) for 30 min. Next, the cells were treated with testosterone (10 µg/ml) plus actinomycin D for an additional 2, 4, and 6 h. Controls cells received actinomycin D plus vehicle (ethanol). The number of 25-hydroxylase and GAPDH transcripts were determined at the end of the treatment periods as described above.

Statistics

All experiments were conducted a minimum of three times. Means were compared for significant differences using one-way ANOVA. A P value <= 0.05 was considered to be significantly different.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Viability

Testosterone had no effect on viability of testicular macrophages at 24 h even at the highest dose (50 µg /ml) (Fig. 1). However, by 72 h, testosterone exerted a cytotoxic effect at both 20 and 50 µg/ml. Because macrophages tenaciously adhere to the culture dishes, they did not detach even after death. Therefore, the total number of cells (dead and alive) among the treatment groups was not significantly different at the end of the experiment, regardless of the degree of cytotoxicity.



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  		FIG. 1. Viability of testicular macrophages treated for 24 and 72 h with various doses of testosterone was determined using the histochemical reagent MTT. Asterisks indicate means that are significantly different from control at P <= 0.05

25-HC Production and Steady-State Levels of 25-Hydroxylase mRNA

Testosterone significantly inhibited production of 25-HC at 10 µg/ml (Fig. 2). It also inhibited the steady-state levels of 25-hydroxylase mRNA following 24-h treatment at 5 and 10 µg/ml (Fig. 3).



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  		FIG. 2. Ability of testicular macrophages to convert cholesterol to 25-HC was assessed during a 20- to 24-h period in the presence or absence of various doses of testosterone. Asterisks indicate means that are significantly different from control at P <= 0.05



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  		FIG. 3. Steady-state levels of 25-hydroxylase mRNA were assessed by "real-time" RT-PCR following treatment of testicular macrophages with various doses of testosterone for 24 h. Asterisks indicate means that are significantly different from control at P <= 0.05

RNA Stability

25-Hydroxylase mRNA from testicular macrophages treated with testosterone or vehicle (ethanol) degraded at similar rates following addition of actinomycin D (Fig. 4). The numbers of 25-hydroxylase transcripts were similar across the times tested in the absence of actinomycin D, indicating that message levels were at steady state. However, we observed the lowest levels of 25-hydroxylase mRNA immediately after plating the cells, with a rise to steady state during the following 6 h, indicating that the cells undergo some trauma during isolation and establishment in culture (data not shown).



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  		FIG. 4. Degradation of 25-hydroxylase mRNA in cultured testicular macrophages treated with or without testosterone (10 µg/ml) was determined in the presence of actinomycin D


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have hypothesized that testicular macrophages are physiologically important in the local control of steroidogenesis in the testis, both because macrophages are located in direct contact with Leydig cells [5] and because Leydig cells develop improperly and testosterone levels fall when macrophages are depleted from the testes [10–13]. We further speculate that 25-HC is, in part, responsible for these actions, because it is readily converted to testosterone [9], inhibits hCG-stimulated steroidogenesis [18], and increases staining of 3ß-hydroxysteroid dehydrogenase in 20-day-old Leydig cells at high doses [22]. The present findings that testosterone inhibits the expression of 25-HC raise the possibility that testosterone feeds back on testicular macrophages to negatively regulate production of 25-HC, suggesting that the relationship between these two diverse cell types is truly interactive and further supporting the concept that these two cell types are functionally coupled. To our knowledge, this is the first report of an effect of testosterone on testicular macrophages, but this steroid has been previously shown to have effects on macrophages in other systems. For example, it has decreased expression of Fc receptors [23], down-regulated nitric oxide synthase [24], modulated inflammatory cytokine production [25], and increased cholesterol ester formation in macrophages from men but not from women [26]. Miller and Hunt [27] have reviewed the effects of testosterone and other steroid hormones on immune functions of macrophages. Whether testicular macrophages have androgen receptors is not known. However, this seems to be likely, because both membrane-bound [28] and nuclear [29, 30] receptors for testosterone have been found in macrophages from other organs. It is particularly interesting to note that androgen receptor expression is greater in macrophages from men than in macrophages from women [31], supporting the observation discussed above concerning the greater effects of testosterone on cholesterol ester formation in men compared to women.

The levels of testosterone needed to inhibit expression of 25-HC were in the µg/ml range in the present study, whereas the levels of testosterone in plasma are in the low ng/ml range [32]. Most androgen-responsive cells in culture respond to testosterone in the ng/ml range [33–35], which is consistent with known levels of serum testosterone as well as with the Kd of the androgen receptor [36]. However, cells in interstitial fluid of the testis are exposed to levels of testosterone reaching the µg/ml range [37]. This represents the average concentration across the concentration gradient, with even higher levels likely to exist within the clusters of Leydig cells where the macrophages commonly reside. Therefore, it may be possible that the high levels of testosterone required to inhibit 25-HC expression, as found in the present study, are attained in situ. Studies assessing intratesticular concentrations of 25-HC production in animals where testosterone levels are experimentally altered should yield more pertinent information concerning the physiological significance of this potential negative-feedback loop for the production of 25-HC.

It is speculated that testosterone inhibits transcription of 25-hydroxylase mRNA, because degradation rates for control and testosterone-treated cells were similar in the presence of actinomycin D. Nuclear run-off assays and analysis of the 25-hydroxylase promoter are underway to further investigate this possibility. It is surprising that message turnover rates were unaffected by testosterone, because androgens have been shown to influence this parameter in some cells [38].

In summary, the results of the present study indicate that production of 25-HC by cultured testicular macrophages is down-regulated by testosterone. Inhibition of 25-HC production by testosterone may have evolved for the purpose of locally controlling the stimulatory paracrine function of testicular macrophages. These data support the growing hypothesis that testicular macrophages play an important role in the local regulation of Leydig cells.


   FOOTNOTES
 
1 Supported by a grant from the National Institutes of Health (HD34708) to J.C.H. Back

2 Correspondence: James C. Hutson, Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430. FAX: 806 743 2990; jim.hutson{at}ttmc.ttuhsc.edu Back

Received: 8 February 2002.

First decision: 4 June 2002.

Accepted: 5 June 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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