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Endocrinology Vol. 138, No. 3 1008-1013
Copyright © 1997 by The Endocrine Society

Articles

Inhibition of Gonadotropin-Induced Testosterone Secretion by the Intracerebroventricular Injection of Interleukin-1ß in the Male Rat1

Andrew V. Turnbull and Catherine Rivier

The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037

Address all correspondence and requests for reprints to: Catherine Rivier, Ph.D., The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: Crivier{at}salk.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The intracerebroventricular (icv) injection of the proinflammatory cytokine interleukin (IL)-1ß is known to significantly decrease plasma LH levels in the male rat, thereby lowering testosterone (T) secretion. We show here that central administration of this cytokine (20–80 ng) also inhibits T secretion in response to human CG (hCG), an effect that is apparent already when IL-1ß is injected 15 min before hCG. This phenomenon is independent of LH secretion because lowering LH levels with the potent GnRH antagonist Azaline B neither mimics nor affects the suppressive influence of icv IL-1ß on the hCG-induced T secretory response. Elevations in plasma corticosterone levels do not seem to play a role either, because icv IL-1ß is able to blunt hCG-induced T secretion in animals whose corticosterone has been removed by adrenalectomy or reduced by the administration of antibodies to CRF. Furthermore, the observation that icv IL-1ß inhibits the T response to hCG before elevations in plasma IL-6 concentrations are detectable, and that central treatment with the cytokine is more effective than iv treatment, indicates that circulating levels of neither IL-1ß nor IL-6 are important mediators of this effect. Collectively, these results lead us to propose that IL-1ß of central origin influences neural pathways linking the brain and the testes, resulting in decreased testicular responses to hCG.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
INFECTIOUS and inflammatory diseases often are accompanied by impaired reproductive functions, including decreased sex steroid levels. One of the most challenging hypothesis proposed to explain this inhibition of the reproductive axis is that immune proteins present in the brain, called cytokines, specifically inhibit the synthesis and release of GnRH (1, 2), the hypothalamic peptide that regulates the activity of the hypothalamic-pituitary-gonadal axis (see Ref.3). This concept is supported by the observation that in the rat, the intracerebroventricular (icv) injection of the prototype inflammatory cytokine interleukin (IL)-1ß significantly lowers plasma LH levels (4, 5, 6, 7). The accompanying decrease in plasma testosterone (T) levels in intact male rats, therefore, has been assumed to be secondary to impaired LH secretion. Whereas this mechanism is undoubtedly operative, we recently made the unexpected discovery that elevations in brain IL-1ß levels also inhibit the T secretory response to human CG (hCG), indicating a loss of testicular responsiveness to this trophic signal (8). The present work was carried out to investigate the mechanisms that could explain this reduced testicular responsiveness. First, by pretreating all rats with a high dose of the potent GnRH antagonist, Azaline B (9), to fully block LH secretion before icv IL-1ß administration, we examined the influence of decreased LH secretion on the blunted testicular activity we had observed. Second, we tested the hypothesis that low T levels might be caused by IL-1ß-induced increases in the secretion of corticosterone (see Ref.10), a steroid that, at least under certain conditions, can impair steroidogenesis (11). Finally, we determined the role played by circulating IL-6, whose release in the periphery is stimulated by the icv injection of IL-1ß (12, 13) and that, like other proinflammatory cytokines (14, 15, 16, 17), could inhibit testicular activity.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Adult male Sprague-Dawley rats (ca 60 days old) were maintained under standard food and lighting regimens (12 h lights:12 h darkness, lights on at 0600). iv cannulae, used for blood sampling, were inserted 48–72 h, and icv cannulae 8–10 days, before the experiments (4, 18). To avoid a possible influence of icv surgery on testicular function, rats prepared for experiments in which the effect of icv IL-1ß were compared with those of iv treatment were all implanted with brain cannulae. Correct placement of the icv cannulae was verified at the end of each assay, and animals with incorrect placement were not used for statistical analysis of the results. Adrenalectomy was carried out under halothane anesthesia 7–10 days before the experiments, and its completeness was verified by the absence of detectable corticosterone levels. In all experiments, blood samples taken via the jugular cannulae were immediately replaced by sterile, apyrogenic saline.

All protocols were approved by the Salk Institute Animal Care and Use Committee.

Treatments
Human recombinant IL-1ß, a generous gift of Dr. S. Gillis (Immunex, Seattle, WA) was dissolved in endotoxin-free water for icv injection and in phosphate-buffered endotoxin-free saline containing 0.1% BSA and 0.01% ascorbic acid for iv treatment. Control rats received the corresponding vehicle. Except for one study (see Fig. 2Go), IL-1ß was injected at 80 ng. For icv treatments, injections were given in a 5-µl vol at the rate of 1 µl/10 sec. The antibodies raised against CRF, a gift from Dr. W. Vale (19, 20), were administered iv at 0.5 ml/kg, a dose that significantly (P < 0.01) reduces corticosterone release in response to all the stimuli that we have studied (C. Rivier, unpublished). The GnRH antagonist, Azaline B, used to block LH release, was synthesized by solid-phase methodology and provided by Dr. J. Rivier (9). It was dissolved in 0.04 M phosphate buffer, pH 7.3, containing 0.1% BSA and 0.01% ascorbic acid. hCG was purchased from Sigma Chemical Co., St. Louis, MO, and diluted in apyrogenic saline.



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  		Figure 2. Effect of the icv injection of the vehicle or IL-1ß (20, 50, or 80 ng) on hCG-induced T secretion. IL-1ß was administered 90 min before hCG. Plasma T levels were measured 90 min after hCG treatment (i.e. 180 min after icv vehicle/IL-1ß). Each point represents the mean ± SEM of five to seven intact male rats. **, P < 0.01 from vehicle or hCG; a, P < 0.01; b, P > 0.05 between groups.

 
Hormones assays
Plasma T, LH, and corticosterone were measured by RIAs as previously described (21, 22). Plasma levels of IL-6 bioactivity were determined by comparing the proliferation of the 7TD1 cell line with the interim international recombinant human IL-6 standard (88/154) (23, 24). Values are quoted as IIU/ml, with the limit of detection of the assay varying between 0.1 and 0.3 IIU/ml.

Statistical analysis
Data were analyzed by one- or two-way ANOVA, followed by Dunnett’s one-sided and/or Duncan’s multiple range test for individual differences.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
T response to hCG
To determine the time-course of the T response to hCG, an initial blood sample was obtained, followed by the iv injection of the vehicle or hCG (0.5–20 U/kg), and testicular response was examined over the following 180 min. A representative curve is illustrated in Fig. 1Go, which shows the T response to 2 U hCG/kg. On the basis of these results, 1 or 2 U hCG/kg were injected iv in all subsequent experiments.



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  		Figure 1. Plasma T response to the iv injection of the vehicle or hCG (2 U/kg, iv). Each point represents the mean ± SEM of five intact adult male rats. **, P < 0.01.

 
Dose-related effect of icv IL-1ß on hCG-induced T secretion
The next series of experiments was designed to determine the minimum dose of IL-1ß, injected icv, that consistently would provide a significant inhibition of hCG-induced T secretion. In this experiment, the vehicle or one dose of IL-1ß (20, 50, or 80 ng) was injected icv at t = 0. The vehicle or hCG was administered iv 90 min later, and plasma samples were obtained every 30 min for 180 min. For the sake of clarity, Fig. 2Go only illustrates T concentrations 90 min after gonadotropin treatment. The icv injection of all three doses of IL-1ß significantly (P < 0.01) decreased basal T levels and inhibited the stimulatory effect of hCG. There was no statistical difference (P > 0.05) between the effect of 50 and 80 ng of the cytokine, though responses were more homogeneous in animals administered 80 ng.

Time-related effect of icv IL-1ß on hCG-induced T secretion
The vehicle or IL-1ß (80 ng) was injected icv 15, 45, or 90 min before iv hCG treatment. Blood samples were obtained subsequently at regular intervals. IL-1ß, injected icv at all 3 time points before hCG, significantly (P < 0.01) blunted basal and hCG-induced T secretion. Fig. 3Go illustrates plasma T levels measured 45 min after the gonadotropin, but similar results were obtained at other time points. IL-1ß, administered 90 min before hCG, was the most effective treatment.



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  		Figure 3. Effect of the icv injection of the vehicle or IL-1ß (80 ng) 15, 45, or 90 min before hCG. Blood samples were taken 45 min after hCG. Each bar represents the mean ± SEM of six intact male rats. **, P < 0.01 from icv vehicle; a, P < 0.05; b, P > 0.05 between groups.

 
Effect of the icv injection of IL-1ß on hCG-induced T release in rats whose LH secretion is blocked
The potent GnRH antagonist, Azaline B [40 µg/kg, a dose that rapidly and markedly decreases LH levels (9)], or its vehicle was administered iv, followed 30 min later by IL-1ß or its vehicle, injected icv. HCG was administered iv 90 min after IL-1ß, at a time when LH levels were 0.28 ± 0.07 ng/ml in controls and 0.08 ± 0.02 ng/ml in rats pretreated with Azaline B. As illustrated in Fig. 4Go, Azaline B had significantly (P < 0.01) lowered plasma T levels at the time of hCG administration but had no impact on the integrated T response to hCG (areas under the curve after hCG injection, minus background, in rats injected with the vehicle icv; controls, 23.4 ± 1.4 ng x h·ml; Azaline B, 20.8 ± 1.2 ng x h·ml; P > 0.05), nor did it affect the inhibitory influence of icv IL-1ß (areas under the curve after hCG injection, minus background, in rats injected with IL-1ß icv: vehicle, 7.5 ± 1.7 ng x h·ml; Azaline B, 6.6 ± 0.8 ng x h·ml; P > 0.05).



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  		Figure 4. Effect of the icv injection of IL-1ß (80 ng) 60 min before hCG in rats preinjected with the vehicle or the GnRH antagonist, Azaline B. Azaline B was injected iv 30 min before IL-1ß. ({circ}), icv vehicle/hCG; (•), Azaline B, icv vehicle/hCG; ({triangleup}), icv IL-1ß/hCG; ({blacktriangleup}), Azaline B, icv IL-1ß/hCG. Each point represents the mean ± SEM of six intact male rats. **, P < 0.01 from the corresponding icv vehicle group.

 
Effect of removing adrenal steroids on testicular response to hCG in rats injected with IL-1ß icv
This experiment comprised intact or adrenalectomized (ADX) rats administered IL-1ß (80 ng, icv) 90 min before hCG (2 U/kg, iv). Intact animals were further subdivided into one group injected with normal sheep serum (0.5 ml/kg, iv) or CRF antibodies (0.5 ml/kg, iv) 60 min before IL-1ß. Corticosterone levels of ADX rats were not detectable at any time and those of intact animals were significantly reduced by removal of endogenous CRF, whether the animals had been injected with the vehicle or IL-1ß (Table 1Go). Fig. 5Go illustrates data obtained in intact rats administered CRF antibodies, and in ADX animals. T levels of intact rats were already significantly (P < 0.01) decreased 45 min after icv IL-1ß (80 ng), whereas those of ADX animals only significantly (P < 0.01) declined by 90 min after cytokine treatment. Furthermore, after hCG treatment, testicular responsiveness was reduced by IL-1ß in both ADX rats and in intact animals administered the vehicle (normal sheep serum) or CRF antibodies iv 3 h before icv treatment.


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  		Table 1. Plasma corticosterone levels in intact rats injected with IL-1ß icv in the presence or absence of endogenous CRF

 


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  		Figure 5. Comparison between the effect of the icv injection of IL-1ß (80 ng) 90 min before hCG on T release in intact rats injected with CRF antibodies (left panel), and in ADX animals (right panel). ({circ}), icv vehicle/hCG; (•), icv IL-1ß/hCG. Each point represents the mean ± SEM of five to seven animals. **, P < 0.01.

 
Comparison between the influence of icv or iv injection of IL-1ß on hCG-induced T release and plasma IL-6 concentrations
An initial experiment was performed to establish the pattern of IL-6 release in rats injected with IL-1ß (Fig. 6Go). Plasma IL-6 concentrations of vehicle-injected rats remained at or below 2 IIU/ml, which represents the normal basal range we detect in controls. In animals injected with IL-1ß icv, a significant rise in plasma IL-6 was first detected 60 (P < 0.05) to 90 (P < 0.01) min post treatment, and levels were still rising by 180 min. Iv IL-ß injection also significantly (P < 0.01) increased plasma IL-6 levels within 60 min, but levels peaked at 90 min and had returned to baseline by 150 min. Also, the magnitude of the IL-6 rise was significantly (P < 0.01) larger after iv than icv treatment.



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  		Figure 6. Effect of the iv or icv injection of IL-1ß (80 ng each) on plasma IL-6 levels. ({circ}), icv vehicle; ({blacksquare}), icv IL-1ß; ({blacktriangleup}), iv IL-1ß. Each point represents the mean ± SEM of six intact male rats. **, P < 0.01 from t = 0.

 
The second experiment compared the T response to hCG in rats injected with IL-1ß either icv or iv 15 min earlier. By 45 min after hCG (i.e. 60 min after IL-1ß administration), icv IL-1ß had produced a small, but not statistically significant, rise in plasma IL-6 levels, whereas iv IL-1ß had induced a large and highly significant (P < 0.01) increase in these concentrations (Fig. 7Go). However, icv IL-1ß was significantly (P < 0.01) more potent than iv IL-1ß at inhibiting the rise in plasma T levels measured at any time after hCG (representative data shown for 45 min after hCG, Fig. 7Go).



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  		Figure 7. Comparison between the effect of icv or iv IL-1ß injection (80 ng) on IL-6 and T levels 45 min after hCG injection. IL-1ß was administered 15 min before hCG. Plasma T levels were measured 45 min after hCG. 0 min corresponds to the time of hCG treatment, i.e. 15 min after IL-1ß treatment. Each point represents the mean ± SEM of six to seven intact male rats. *, P < 0.05; **, P < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We show here that as previously reported (8), the icv injection of IL-1ß significantly decreased the T response to hCG in male rats. Furthermore, we demonstrate that this effect is independent of changes in LH levels, because it is neither mimicked nor affected by lowering levels of LH with a potent GnRH antagonist. Indeed, even though both the antagonist alone and IL-1ß alone had reduced plasma T levels by the time hCG was injected, only rats administered IL-1ß centrally showed a blunted testicular response. This indicates that in itself, lowering LH concentrations does not interfere with the testes’ response to its trophic signal.

We investigated several hypotheses to account for this LH-independent inhibition of the testicular response to hCG produced by icv IL-1ß. First, we thought that cytokine-induced increases in plasma corticosterone levels, a steroid that interferes with gonadal activity (11), might play a role. Though most of the in vivo work reporting an inhibitory influence of ACTH/adrenal steroids on testicular function has relied on long-term studies (25, 26), we still thought it possible that acute increases in corticosteroid levels might influence T secretion. This hypothesis was tested by comparing the influence of icv administered IL-1ß in rats whose plasma glucocorticoids had been removed by adrenalectomy or reduced by a CRF antiserum. Similar results were obtained regardless of the presence or absence of this steroid, a finding that does not support the hypothesis. In view of recent observations that large-molecular weight substances, such as antibodies (27) or cytokines (13, 28), injected icv quickly reach the general circulation, we also considered the possibility that by leaking to the periphery, icv IL-1ß could directly inhibit steroidogenic pathways (14, 15, 16, 17). However, the observation that iv treatment with this cytokine was significantly less potent than icv treatment makes it highly unlikely that decreased T release was primarily caused by the ability of icv IL-1ß to reach the gonads. We also thought that IL-6 present in the circulation of rats injected with IL-ß icv [(13, 29) and present work] might act directly on the testes. We show here that icv-injected IL-ß was more effective than iv treatment in reducing testicular responsiveness despite the fact that the magnitude of IL-6 release over the time course of our experiments was consistently larger in rats administered IL-1ß systemically. If increased blood-borne IL-6 levels were the leading mechanism responsible for the decreased T response, the opposite should be true. Furthermore, the icv injection of IL-1ß shortly before hCG was able to blunt the stimulatory effect of the gonadotropin before measurable increases in plasma IL-6 were noted. Collectively, these results strongly suggest that the ability of icv IL-1ß to interfere with hCG-induced T release is not directly related to increases in circulating IL-6.

It remains possible that the concentration of one or more as yet unidentified factors (e.g. cytokines) other than IL-6 are elevated to a greater extent by icv than iv IL-1ß, and subsequently inhibit testicular responsiveness. However, an intriguing possibility, suggested in particular by the rapidity of the inhibitory influence of icv injected IL-1ß, is that IL-1ß might exert its influence via a direct neural pathway between the central nervous system (CNS) and the testes. In female rats, evidence for a link between the endocrine brain and the gonads has been proposed on the basis of experiments showing that electrical stimulation of the medial basal prechiasmatic area of hypophysectomized, ADX animals increased estrogen and progesterone release and that this response was abolished by ovarian denervation (30). Complete deafferentation of the medial-basal hypothalamus also has been reported to prevent the development of compensatory ovarian hypertrophy after unilateral ovariectomy (31), whereas ovarian nervotomy significantly decreased gonadal GnRH and ß-adrenergic receptors (32). A neural connection between the brain and the testes also has been proposed, which comprises both afferent and efferent pathways (33, 34, 35). In mammals, these pathways are both serotonergic (36) and catecholaminergic (37, 38), although, at least in the Rhesus monkey, the latter innervation is more prevalent in prepubertal than in adult animals. Testicular nerves are thought to control vascular tone, seminiferous tubules movements, the sensation of pain, and, of significance for our work, Leydig cell function. Indeed, in the rat, bilateral denervation blocks the early stress-induced rise in T levels (39), whereas excision of spermatic nerves inhibits hCG-induced T secretion and decreases LH receptors (40).

If true, this concept suggests a novel mechanism through which stressful stimuli can interfere with testicular function. IL-1ß is constitutively expressed in the normal brain (41, 42), and its production is increased in response to CNS infection, inflammation, or trauma (43, 44, 45, 46, 47, 48). In addition, there is evidence that levels of this particular cytokine may also be augmented in the CNS in response to endotoxemia (49, 50, 51), peripheral inflammation (52), and after exposure to nonimmune stressors (53, 54). Collectively, these data suggest that CNS IL-1ß synthesis may be regulated by a variety of homeostatic threats. Little is known regarding the ability of such conditions to reduce testicular responsiveness independent of circulating cytokines, and of the participation of brain IL-1ß, should this be the case. The present study nevertheless clearly demonstrates that it is important to consider such a mechanism in interpreting changes in gonadal function induced by a variety of noxious stimuli.


   Acknowledgments
 
The authors are indebted to S. Johnson, M. Wozniak, J. Janas, and Y. Haas for excellent technical assistance; to Dr. S. Gillis for IL-1ß; to Dr. W. Vale for CRF antibodies; and to Dr. J. Rivier for Azaline B.


   Footnotes
 
1 This work was supported by NIH Grant HD-13527 and the Foundation for Research. Back

Received October 3, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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