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Hypothalamic Interleukin-1ß and Tumor Necrosis Factor-, But Not Interleukin-6, Mediate the Endotoxin-Induced Suppression of the Reproductive Axis in Rats

Clinical Research Center (H.W.) and Rehabilitation Center (Y.H.), International University of Health and Welfare, Otawara, Tochigi 324-8501, Japan

Address all correspondence and requests for reprints to: Hajime Watanobe, M.D., Division of Internal Medicine, Clinical Research Center, International University of Health and Welfare, 2600-1 Kitakanemaru, Otawara, Tochigi 324-8501, Japan. E-mail: watah{at}iuhw.ac.jp.

	Abstract

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It is well established that endotoxemia disrupts reproductive capability, and several proinflammatory cytokines, especially IL-1ß, IL-6, and TNF- in the brain, have been implicated in this endocrine aberration. However, no previous study has directly compared the effects of the three major proinflammatory cytokines (IL-1ß, IL-6, and TNF-) on the in vivo release of hypothalamic GnRH, a secretagogue of LH from the pituitary. Therefore, in this study, we addressed this issue with two complementary approaches involving push-pull perfusion in freely moving ovariectomized female rats. First, we examined the effects of systemic lipopolysaccharide (LPS) treatment on the release of plasma LH, and of GnRH, IL-1ß, IL-6, and TNF- in the hypothalamic medial preoptic area (MPOA), where the majority of GnRH neuronal perikarya are located. LPS inhibited the secretion of both LH and GnRH and concomitantly stimulated the release of all three cytokines. We next tested the effects of direct MPOA perfusion with the respective cytokines (at three different concentrations each) on the GnRH and LH secretion. IL-1ß and TNF-, at the concentrations that were observed in the MPOA after the LPS injection, were equipotent in inhibiting the GnRH-LH system, whereas IL-6 was ineffective (even at a supraphysiological concentration). These results strongly suggest that IL-1ß and TNF- may represent the major proinflammatory cytokines mediating the LPS-induced suppression of GnRH and LH release, whereas the role of IL-6 seems to be insignificant.

	Introduction

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THERE IS CLINICAL evidence that infections and inflammatory diseases are often accompanied by impaired reproductive function (1, 2). Accumulating evidence suggests that lipopolysaccharide (LPS), a glycolipid of gram-negative bacteria widely used to mimic septicemia, disrupts the reproductive capability indirectly by intermediary molecules comprising proinflammatory cytokines, prostaglandins, endogenous opioid peptides, and catecholamines (3, 4, 5, 6). Although adrenal glucocorticoids, which increase upon LPS administration, have been considered as another potential mediator of the LPS-induced hypogonadal state (5, 7), recent studies (including ours) indicate that glucocorticoids do not play a significant role in mediating the acutely suppressed release of GnRH and LH induced by LPS (8, 9). In the present study, we focused on the involvement of three major proinflammatory cytokines (IL-1, IL-6, and TNF-) (10), because they serve as pivotal and early immune inhibitors of reproductive functions, by which the production of prostaglandins, opioid peptides, and catecholamines is subsequently stimulated (3, 4, 5, 6).

Published studies have shown that IL-1 (especially IL-1ß, compared with IL-) potently suppresses LH release through blockade of GnRH secretion (11, 12, 13, 14, 15, 16, 17, 18, 19, 20). One recent report suggested that IL-1ß might suppress GnRH neuronal activity by inhibiting the translational efficiency of the GnRH mRNA (21). By contrast, previous reports concerning the effects of IL-6 and TNF- on the GnRH-LH system have been contradictory. Although one in vivo study reported that central administration of IL-6 was inhibitory to LH secretion (12), other reports demonstrated no effect of IL-6 in vivo (4, 22). Similarly, the reported actions of IL-6 on pituitary LH release in vitro vary from stimulatory (23) to inhibitory (24), or no effect (22). A recent report (24) suggested that there may be sex-related differences in the effects of IL-6 on pituitary LH release in rats in vitro. With respect to TNF-, several in vivo studies agreed that TNF- is inhibitory to the GnRH-LH system (4, 12, 25, 26). However, under in vitro conditions, one study demonstrated TNF- to be stimulatory to LH secretion (27), whereas other investigators reported that TNF- was without effect on the basal LH release although the cytokine did inhibit the GnRH-induced LH secretion (28). The above-mentioned in vitro study (24) also demonstrated that TNF- did suppress the GnRH-stimulated LH release in female rats but not in males. These inconsistencies, especially regarding the actions of IL-6 and TNF-, may derive from the differences in experimental protocols employed (including in vivo vs. in vitro conditions) and the species and gender of animals used, and also may derive from the use of homologous vs. heterologous cytokines for administration.

Therefore, in this study, we aimed to explicitly examine the involvement and relative importance of brain IL-1ß, IL-6, and TNF- in the LPS-induced suppression of the reproductive system in rats in vivo, implementing two complementary approaches involving the push-pull perfusion (PPP) technique. Because previous studies strongly suggested that IL-1ß primarily acts at the level of GnRH perikarya in the medial preoptic area (MPOA) of the hypothalamus to inhibit this neurohormone’s release (17, 18, 20), we first attempted to determine the local concentrations of IL-1ß, IL-6, and TNF- attained in the MPOA after systemic LPS treatment caused a significant inhibition of GnRH and LH release. Next, we directly infused, into the MPOA, various concentrations of the respective cytokines (including the concentrations that were detected in the MPOA after the LPS injection) and compared their effects on the GnRH-LH system. We thus obtained data strongly suggesting that IL-1ß and TNF- are almost equipotent in suppressing the reproductive system, whereas IL-6 is without effect in this regard.

	Materials and Methods

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Animals and PPP protocol
All the following procedures were approved by the Ethical Committee for Animal Experimentation of the International University of Health and Welfare. Animals were maintained in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Female rats (240–250 g) of the Wistar strain were used. They were housed in an air-conditioned room (20–24 C) with controlled lighting (light on from 0800–2000 h) and were given free access to laboratory chow and tap water. Two weeks before PPP, the animals were bilaterally ovariectomized under anesthesia with sodium pentobarbital (40 mg/kg body weight, ip). At the same time, a guide cannula with a removable inner stylet was stereotaxically implanted in the MPOA consistently on the right side. Stereotaxic coordinates for cannula placement were the same as in our previous report (29). The PPP cannulae used were the same as described in our previous studies (30, 31, 32). The device was fixed onto the skull with anchor screws and dental cement. Seven days after ovariectomy and placement of the PPP cannula, the body weight of each animal was recorded to ensure that it had returned to that of presurgery. Animals with decreased body weights were not used for the experiment. Two days before PPP, all animals were implanted with a jugular vein catheter filled with heparin solution (5 IU/ml) under pentobarbital anesthesia.

At about 0800 h on the day of PPP, an extension of the jugular vein catheter was installed for frequent blood sampling, and the inner stylet within the brain guide cannula was replaced with the inner cannula perfusion assembly. Thereafter, artificial cerebrospinal fluid (ACSF), with the same composition as in our previous studies (30, 31, 32), was infused through the push cannula and collected from the pull cannula at a flow rate of 15 µl/min. The dead space of the pull system (from the tip of the guide cannula to the distal end of the pull tubing) was adjusted to 225 µl (corresponding to a 15-min period of perfusion), so that a blood sample could be drawn in the middle of each time period for perfusate collection (30 min). Until the experiment was over, the animals were deprived of food, although they were given free access to drinking water. After a 3-h equilibration period, blood samples (100 µl) to measure LH were collected from the freely moving animals every 6 min, between 1100–1700 h. An equivalent volume of red blood cells taken from donor rats was suspended in normal saline and replaced through the jugular vein catheter after each blood collection. Perfusion fractions (450 µl) were collected every 30 min, over a total period of 390 min (1100–1730 h). The reason for collecting a perfusate also between 1700–1730 h was the existence of the above-mentioned dead space within the pull system. The collected perfusates were immediately frozen on dry ice, lyophilized, and stored at -70 C until assayed for GnRH, IL-1ß, IL-6, and TNF-. The blood was collected in tubes containing EDTA-2Na (2.5 mg/ml blood) and was centrifuged, and the plasma was stored at -70 C until assayed for LH. Within 30 min after completion of the experiment, the animals were killed by rapid decapitation, and their brains were removed and stored at -70 C for histological examination.

Experiment I: systemic endotoxin administration
At 1400 h, 100 µg/kg body weight of LPS (Escherichia coli, serotype O127:B8, Sigma, St. Louis, MO) was injected iv as a bolus. LPS was dissolved in normal saline (vehicle) just before use. Animals that were given the vehicle only served as controls.

Experiment II: direct infusion of cytokines into the MPOA
Using the PPP system, we directly perfused the MPOA with rat recombinant IL-1ß, IL-6, and TNF- at three different concentrations each: IL-1ß (10, 40, and 100 pg/ml); IL-6 (40, 150, and 400 pg/ml); and TNF- (7, 15, and 40 pg/ml). All cytokines were purchased from BioSource International (Camarillo, CA), and their concentrations infused were determined based on the results from experiment I. The cytokines were dissolved in the ACSF, immediately before infusion, during the period 1400–1730 h, and control animals were perfused with the pure ACSF during the same period. The actual time of day during which the cytokines were infused was between 1345–1715 h, because the dead space of the push system (from the tip of the push cannula to the distal end of the push tubing) was adjusted to 225 µl (corresponding to a 15-min period of perfusion).

Assays
The lyophilized perfusates were reconstituted with 450 µl of an assay buffer (0.1% BSA, 100 mM PBS, 0.1% sodium azide, 0.1% Triton X-100, pH 7.4) and subjected to the RIA of GnRH and to the ELISAs of rat IL-1ß, IL-6, and TNF-. A 100-µl aliquot was applied to each of these four assays. Iodinated GnRH was purchased from the NEN Life Science Products (Boston, MA), and GnRH antisera and GnRH as the standard from the Peptide Institute, Inc. (Osaka, Japan). The GnRH antibody was used at the final concentration of 1:480,000. The sensitivity of the GnRH RIA was 1.5 pg/ml (0.15 pg/tube). ELISAs for the three cytokines were performed using kits produced by BioSource International. The sensitivities of these assays were 3.0, 8.0, and 4.0 pg/ml for IL-1ß, IL-6, and TNF-, respectively. In a preliminary study, we examined the recovery of IL-1ß, IL-6, and TNF- after infusing them through the entire PPP system at room temperature, and we found that a period of at least 3 h did not affect the recovery of either cytokine. GnRH and the cytokines were also measured in reconstituted lyophilizates from blank perfusates (five samples per rat) containing 450 µl of the pure ACSF, and their mean values were subtracted from the levels in all the actual perfusates from every animal. LH levels were determined by RIA using reagents kindly donated by Dr. A. F. Parlow (National Institute of Diabetes and Digestive and Kidney Diseases; Torrance, CA). Rat LH-reference preparation-3 was used as the standard, and the sensitivity of the LH assay was 0.2 ng/ml. In all the hormone and cytokine assays, samples from individual rats were analyzed within the same assay, and both intraassay and interassay coefficients of variation were less than 10%.

Histology
Histological examination of the PPP cannula placement was done in the same manner as we reported previously (30). Only animals that had the tip of the cannula within the MPOA contributed to the data given in Results.

Statistical analyses
To determine whether observed temporal fluctuations in plasma LH constituted endogenous pulses, the results were analyzed by the cluster analysis method (33). A t statistic of 2.0 was selected to maintain a maximal false-positive rate of 2.5% or less, by using cluster sizes of one or two in the nadir and peak. Results were expressed as the mean ± SEM. For the purpose of detecting significant alterations within groups, data of individual experimental groups were analyzed by two-way ANOVA with repeated measures. One-way ANOVA was used to compare data among the different groups. When significant F values were obtained, a Bonferroni multiple-comparisons test was performed. Differences were considered significant if P was smaller than 0.05.

	Results

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Experiment I: effects of a single iv administration of LPS on the secretion of plasma LH and those of GnRH and cytokines in the MPOA
The effects of systemic LPS treatment on LH secretion, as analyzed at 6-min intervals, are shown in Figs. 1 and 2. Figure 1 shows the individual LH release profiles of two representative animals that received LPS or saline, respectively. It is evident that a single LPS injection promptly abolished pulsatile LH secretion. Analysis of the group data revealed that this effect of LPS was statistically significant (Fig. 2). Although saline did not affect mean and nadir levels of LH or the frequency and amplitude of LH pulses, LPS caused significant decreases in all these parameters. Figure 3 shows the effects of LPS treatment on the release of GnRH, IL-1ß, IL-6, and TNF- in the MPOA. The saline injection was without effect on the local release of GnRH or of any of the cytokines. In contrast, LPS caused a significant decrease in GnRH output between 1500–1700 h, compared with saline. The levels of all three cytokines in the MPOA started increasing 30 min after LPS, and peak values were observed 90–120 min after the injection. It was noted that the first significant elevation of every cytokine preceded the first significant decrease in GnRH output by 30 min. The immunoreactive concentrations and temporal patterns of all three cytokines in the MPOA were very similar to our previous measurements in the hypothalamic paraventricular nucleus after systemic LPS treatment in rats (34).

View larger version (38K): [in this window] [in a new window]   FIG. 1. Representative profiles of plasma LH in two ovariectomized female rats that received the iv bolus injection of LPS (100 µg/kg body weight) or saline, respectively. In this figure and Fig. 3, the arrow indicates the time point when LPS or saline was administered. In this figure and Figs. 4 and 7, the stars indicate significant LH pulses detected by Cluster analysis.

View larger version (24K): [in this window] [in a new window]   FIG. 2. Characteristics of LH secretion before and after the iv injection of LPS (100 µg/kg body weight) or saline in ovariectomized female rats. Open column, Saline (n = 9); filled column, LPS (n = 10); , statistically significant vs. the Before value of the same group and the After value of the saline group.

View larger version (24K): [in this window] [in a new window]   FIG. 3. Effects of the iv administration of LPS (100 µg/kg body weight) on the release of GnRH, IL-1ß, IL-6, and TNF- in the MPOA perfusates collected from ovariectomized female rats. Open circle, Saline (n = 9); filled circle, LPS (n = 10). In this figure and Figs. 6 and 9: 1) the time of the perfusate collection is shifted 15 min ahead of the actual time of perfusion, because the dead space of the pull system (225 µl) corresponds to a 15-min period of perfusion (flow rate, 15 µl/min); 2) measurements of GnRH and the three cytokines in perfusates are expressed as point values at the center of their collection periods; 3) the horizontal dotted lines indicate the limits of detection for GnRH and cytokines; and 4) where SEs are not shown, they were smaller than the symbols. , Statistically significant vs. the saline group.

View larger version (30K): [in this window] [in a new window]   FIG. 4. Representative profiles of plasma LH in four ovariectomized female rats that received the three different concentrations of IL-1ß or ACSF, respectively, into the MPOA. In this figure and Figs. 6, 7, and 9, the horizontal filled bars indicate the period during which cytokine or ACSF (vehicle) was infused.

View larger version (48K): [in this window] [in a new window]   FIG. 5. Characteristics of LH secretion before and during the IL-1ß or ACSF infusion into the MPOA in ovariectomized female rats. Open column, ACSF (vehicle, n = 9); single-hatched column, IL-1ß (10 pg/ml, n = 8); cross-hatched column, IL-1ß (40 pg/ml, n = 9); filled column, IL-1ß (100 pg/ml, n = 10); , statistically significant vs. the Before value of the same group and the During values of the ACSF and IL-1ß (10 pg/ml) groups; , statistically significant vs. the Before value of the same group and the During values of the remaining three groups.

View larger version (23K): [in this window] [in a new window]   FIG. 6. Effects of various concentrations of IL-1ß infused into the MPOA on the local release of GnRH in ovariectomized female rats. Open circle, ACSF (vehicle, n = 9); filled circle, IL-1ß (10 pg/ml, n = 8); filled triangle, IL-1ß (40 pg/ml, n = 9); filled square, IL-1ß (100 pg/ml, n = 10). During the period 1430–1700 h, the perfusate IL-1ß levels after infusing the three different concentrations of the cytokine were significantly different from each other. , Statistically significant vs. the IL-1ß (10 pg/ml) group; , statistically significant vs. the IL-1ß (40 pg/ml) and IL-1ß (100 pg/ml) groups.

Figure 7 shows the effects of direct TNF- infusion into the MPOA on LH secretion in four representative animals that received different treatments. The individual data suggested that both the 15 and 40 pg/ml of TNF-, but not the 7-pg/ml dose, were inhibitory to pulsatile LH secretion. Analysis of the group data indicated that these effects of TNF- were statistically significant (Fig. 8). Both the 15- and 40-, but not the 7-pg/ml concentration of TNF-, significantly reduced the mean and nadir LH levels as well as the frequency and amplitude of LH pulses, except for the insignificant effect of 15 pg/ml TNF- on nadir LH levels. Figure 9 shows the effects of direct TNF- infusion into the MPOA on the local release of GnRH. As seen in the perfusions with IL-1ß and IL-6, the highest measurable level of TNF- in the perfusates was 70–80% of the infused concentration for all three doses. Compared with ACSF, any concentration of TNF- significantly decreased GnRH release in the MPOA. The inhibitory effects of 15 and 40 pg/ml of TNF- were significantly larger than that of the 7-pg/ml dose.

View larger version (32K): [in this window] [in a new window]   FIG. 7. Representative profiles of plasma LH in four ovariectomized female rats that received the three different concentrations of TNF- or ACSF, respectively, into the MPOA.

View larger version (43K): [in this window] [in a new window]   FIG. 8. Characteristics of LH secretion before and during the TNF- or ACSF infusion into the MPOA in ovariectomized female rats. Open column, ACSF (vehicle, n = 9); single-hatched column, TNF- (7 pg/ml, n = 9); cross-hatched column, TNF- (15 pg/ml, n = 8); filled column, TNF- (40 pg/ml, n = 10). The data of the ACSF group are repeated from those in Fig. 5. , Statistically significant vs. the Before value of the same group and the During values of the ACSF and TNF- (7 pg/ml) groups.

View larger version (31K): [in this window] [in a new window]   FIG. 9. Effects of various concentrations of TNF- infused into the MPOA on the local release of GnRH in ovariectomized female rats. Open circle, ACSF (vehicle, n = 9); filled circle, TNF- (7 pg/ml, n = 9); filled triangle, TNF- (15 pg/ml, n = 8); filled square, TNF- (40 pg/ml, n = 10). During the period 1430–1700 h, the perfusate TNF- levels after infusing the three different concentrations of the cytokine were significantly different from each other. The GnRH data of the ACSF group are repeated from those in Fig. 6. , Statistically significant vs. the TNF- (7 pg/ml) group; , statistically significant vs. the TNF- (15 pg/ml) and TNF- (40 pg/ml) groups.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Therefore, we next examined the effects of direct MPOA perfusions with IL-1ß, IL-6, and TNF- individually on the secretion of hypothalamic GnRH and plasma LH. We found that both IL-1ß and TNF- were able to dose-dependently inhibit the GnRH and LH release on their own, although the middle and highest concentrations of either cytokine had a similar suppressive effect. Because the lowest infused concentrations of both IL-1ß (10 pg/ml) and TNF- (7 pg/ml) were set to levels corresponding to those found in the very first MPOA perfusate after the LPS injection (Fig. 3), the current results strongly suggest that both IL-1ß and TNF- may serve significant intermediary roles in the LPS-induced suppression of hypothalamic GnRH, and thereby of plasma LH.

However, it deserves attention that the lowest infused concentrations of both IL-1ß and TNF- were without effect on the pulsatile LH release, which was only suppressed by the other two higher concentrations of either cytokine. This differential sensitivity of GnRH and LH to both IL-1ß and TNF- was probably due to the inherent limitations of the PPP technique employed in the present study. Inasmuch as the PPP allows us to perfuse only a small restricted area of a single side of the hypothalamus, it is not surprising that the suppressed GnRH release in the unilateral MPOA, induced by the lowest concentrations of IL-1ß and TNF-, did not lead to decreased LH levels.

In contrast to the infusions of IL-1ß and TNF-, the direct infusion of IL-6 into the MPOA was without effect on the release of either GnRH or LH, even at its highest concentration infused. These results suggest that, although systemic LPS treatment elevates IL-6 concentrations in the MPOA, this increase in IL-6 may not be involved in the LPS-induced suppression of the reproductive hormones.

The marked inhibitory effect of IL-1ß on the GnRH-LH system demonstrated in this study is in agreement with the previous reports by other investigators (11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). Regarding TNF-, most of the published studies (4, 12, 24–26, 28), except one (27), reported that this cytokine was inhibitory to the GnRH-LH system, in conformity with the present data. In this context, it is worth noting that several previous studies found TNF- to be less effective than IL-1ß in suppressing the reproductive axis (4, 12), which contrasts with the present finding that the two cytokines have almost equipotent actions. Similarly, the lack of involvement of IL-6 in the LPS-induced suppression of GnRH and LH release that we found, is in agreement with part of the literature (4, 22), but not all (12, 23, 24). Although we have no clear explanations for these apparent discrepancies, we must underscore the implications of the present study by highlighting the fact that we, for the first time, compared directly the effects of IL-1ß, IL-6, and TNF- on the secretion of hypothalamic GnRH and plasma LH under the unanesthetized in vivo condition in rats. In addition, as discussed below, to better understand the role of individual cytokines in regulating reproductive functions, we may also need to consider the interactions among different cytokines that have been demonstrated under various physiological and pathological circumstances.

LPS is known to increase the synthesis and secretion of an array of proinflammatory and anti-inflammatory cytokines (10). These cytokines can affect the reproductive system on their own, and there also exist multiple interactions among various cytokines (3, 4, 5). In this context, it is noteworthy that IL-1 can induce the expression of IL-6 receptors in the brain (43, 44). Because we did not examine such a synergistic action among IL-1ß, IL-6, and TNF- in this study, the possibility still remains that IL-6 can significantly inhibit the GnRH and LH release in endotoxemia, the condition that is commonly accompanied by increased circulating levels of various proinflammatory cytokines, including IL-1ß. Furthermore, it is known that IL-6 inhibits the production of IL-1 and TNF- (45, 46), and nearly all biological responses to either IL-1 or TNF- can be enhanced when the two are coadministered (47). It is thus very likely that the final outcome of the reproductive axis modulation by LPS is determined by the net effect of the interactions among various cytokines. This synergism among different individual cytokines could account for the present finding that the degree of suppression of GnRH and LH, after systemic LPS treatment, was still larger than that caused by the highest infused concentration of either IL-1ß or TNF-, both of which maximally inhibited the reproductive hormones when infused individually.

In summary, in this study, we examined and compared the relative contribution of IL-1ß, IL-6, and TNF- to the well-known suppression of reproductive functions induced by LPS, using the PPP technique in rats in vivo. It was found that both IL-1ß and TNF- exert significant and almost-equipotent inhibitory effects on the GnRH-LH system, whereas the participation of IL-6 seems to be insignificant. It is very probable that IL-1ß and TNF- in the brain act both independently and cooperatively to inhibit the reproductive competence under conditions of endotoxemia.

	Acknowledgments

 
We thank the National Hormone and Pituitary Program of the National Institute of Diabetes and Digestive and Kidney Diseases and Dr. A. F. Parlow for the generous donation of reagents for rat LH RIA. We also thank Dr. Satoshi Habu (Department of Medicine, Aichi Medical University School of Medicine, Japan) for his invaluable assistance with this work.

	Footnotes

 
This work was supported, in part, by grants-in-aid from the Japan Society for the Promotion of Science (12671072 and 14571071) and the International University of Health and Welfare.

Abbreviations: ACSF, Artificial cerebrospinal fluid; LPS, lipopolysaccharide; MPOA, medial preoptic area; PPP, push-pull perfusion.

Received May 27, 2003.

Accepted for publication July 11, 2003.

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