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Ligand Pharmaceuticals (K.O.), Department of Pharmacology, San Diego, California 92121; and The Clayton Foundation Laboratories for Peptide Biology (C.R.), The Salk Institute, La Jolla, California 92037
Address all correspondence and requests for reprints to: Catherine Rivier, The Clayton Foundation Laboratories for Peptide Science, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: crivier{at}salk.edu
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Abstract |
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-methyl-4-[2-methyl-propyl]benzeneacetic acid; sodium salt),
which did not, in itself, alter the stimulatory effect of hCG on
testosterone release in control rats, modestly, but significantly
(P < 0.05) reversed the inhibitory influence of
IL-1ß. In contrast, blockade of brain receptors for CRF was unable to
alter the effect of IL-1ß, as were lesions of the ventromedial
hypothalamic nucleus, a brain area implicated in the control of ovarian
function. Blockade of ß-adrenergic receptors significantly prevented
the decrease in testicular responsiveness induced by the icv injection
of IL-1ß. Finally, the central injection of the ß-adrenergic
agonist isoproterenol, as well as that of norepinephrine, mimicked the
ability of icv IL-1ß to blunt testicular secretory activity and
produced a marked (P < 0.01) decrease in the
response to hCG within 5 min of their administration. We propose that the explanation that best fits our findings is that the icv injection of IL-1ß activates a neural, catecholamine-dependent pathway that connects the brain and the testes independently of the pituitary.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and IL-6) to decrease the
secretion of GnRH and LH is well established (reviewed in Ref. 1). This
effect was originally demonstrated in gonadectomized rats and in
proestrous females, in which LH levels are easily measured. Subsequent
experiments were carried out in intact males, and in this model, the
low plasma testosterone (T) levels of rats injected with IL-1ß icv
were attributed to decreased LH secretion. We reasoned that if this was
the case, exogenous gonadotropin administration should reverse the
effect of the cytokine. Much to our surprise, this was not the case,
and even relatively large doses (up to 10 mU) of human CG (hCG) did not
restore normal T levels. We reported that this blunted testicular
responsiveness was significant within 15 min of IL-1ß administration
and persisted for at least 90 min (2, 3). We also demonstrated that
this effect was independent of decreased LH levels and increased
corticosterone release, and that it precedes the appearance of IL-6 in
the circulation (3). The effectiveness of icv IL-1ß in
adrenalectomized rats (3) also suggested that adrenal catecholamines
were not of primary importance. Finally, we considered the potential
role of PRL, a pituitary hormone reported by a few investigators (4, 5)
to be released by IL-1ß and which interferes with testicular activity
(6). Our earlier studies had failed to indicate significant increases
in the plasma PRL levels of adult male rats injected with IL-1ß icv
(7). These experiments had used smaller doses of cytokine than the one
chosen in the present context. We therefore measured PRL release in the
protocol described here, and again we failed to note measurable
increases (C. Rivier, unpublished). Indeed, if anything, PRL levels
exhibited a slight (P < 0.05) decrease over the
time-course of the assays, which confirms the results we had previously
reported (7). These results seem to rule out a role of this pituitary
hormone in our paradigm. Overall, these findings and the ones we and
others previously reported indicate that the icv injection of IL-1ß
can lower T levels through two mechanisms, one that is secondary to
decreased LH release, and one that is independent of pituitary
activity. One of the most intriguing hypotheses suggested by our results stems from the extreme rapidity with which icv IL-1ß blunted testicular activity. As further evidence for this rapidity (3), we show here that hCG-induced T secretion is already significantly reduced within 5 min of IL-1ß administration. This led us to consider the possibility that this cytokine might influence testicular activity through neuronal inputs. Neurons from pelvic ganglia are the primary source of efferent postganglionic fibers that supply the testes of the adult rat (8). These sympathetic fibers are thought to be important for the normal activity of Leydig cells (8, 9, 10, 11), particularly through the maintenance of an adequate number of LH receptors (12, 13). The fact that pelvic ganglia are supplied, in part, by nerves such as the vagus (14), suggests the possibility that the testes may be influenced by neural pathways. Such a direct connection has indeed been invoked as an important mechanism controlling Leydig cell functions (15).
If icv-injected IL-1ß alters testicular responsiveness to hCG by acting on neural pathways between the hypothalamus and the gonads, this could be achieved through several mechanisms. The interstitial fluid surrounding the testicular cells contains secretagogues that come from the circulation, are released by fibers innervating the capsule, and/or are produced locally. The mechanisms on which we focused in the present work, primarily include the signals that might be released by IL-1ß in the brain. Prostaglandins, for example, whose levels increase in the brain in response to proinflammatory cytokines (16), mediate many of the biological effects of these proteins (see Refs. 1, 17). Surprisingly, however, the studies we describe here indicate that activation of cyclooxygenase-dependent pathways plays only a modest role in our model. We therefore considered the potential importance of CRF, which is suggested by the ability of IL-1ß to increase levels of this peptide in the brain (18, 19), and by the known inhibitory influence it exerts on reproductive functions (see Refs. 1, 20). However, our data clearly indicate that CRF is unlikely to play a major role in explaining why the T response to rats injected with IL-1ß icv is dramatically decreased. In view of the participation of catecholamines in testicular innervation (10) and of the stimulatory action of IL-1ß on bioamine levels in the brain (18, 19, 21, 22, 23, 24, 25), we then explored the mediating effect of these secretagogues. In this article, we provide evidence that activation of ß-adrenergic receptors, in particular, seems of major importance for the inhibitory effect of icv IL-1ß. Finally, the last series of experiments we describe represents an attempt to identify the origin of the neural connections to the testes. Specifically, we investigated the importance of the ventromedial hypothalamus (VMH) because, in the female rat, this brain region modulates sex steroid production independently of changes in pituitary function (26).
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Materials and Methods |
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60 days old) were maintained
under standard food and lighting regimens (12-h light, 12-h darkness;
lights on at 0600 h). iv cannulae, used for blood sampling, were
inserted 48–72 h before the assays, while the rats were under
halothane anesthesia. icv cannulae were implanted 8–10 days before the
experiments, under anesthesia induced by a mixture of ketamine,
xylazine, and acepromazine (50, 10, and 2 mg/ml, respectively; 0.5
ml/rat) (3). With the incisor bars placed at 3.3 mm below the
interaural lines (horizontal zero), the stereotaxic coordinates from
bregma were as follows: anteroposterior, -1.7 mm; lateral, ± 0.4 mm;
dorsoventral, -7.9 mm. For experiments investigating the role of
central blockade of adrenergic receptors, two icv treatments were
necessary, i.e. the antagonist and IL-1ß. In our
experience, administering two icv treatments from the same icv cannula
is not reliable enough to ensure that each treatment is injected
separately. Rats used for these studies were therefore equipped with
two icv cannulae, one in each ventricle. Both single- and double-icv
cannulae were purchased from Plastics One (Roanoke, VA). Single
treatments were injected in a 5-µl vol, and double treatments in a
3-µl vol each. The rate of infusion was 1 µl/10 sec. 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. All protocols were approved by the Salk Institute Institutional Animal Care and Use Committee.
IL-1ß injection
Human recombinant IL-1ß, a generous gift of Dr. S. Gillis
(Immunex, Seattle, WA), was dissolved in endotoxin-free water. It was
administered icv at 80 ng, a dose that produces maximum inhibition of
the testicular response to hCG (3). Control rats received the
corresponding vehicle. In general, IL-1ß was administered 60 min
before hCG. Although, as shown below, a significant decrease in the T
response to the gonadotropin can be observed at earlier times, the
60-min time point was chosen because it provides more homogeneous and
reliable responses.
Reagents
All of the following reagents were injected either iv through
the jugular vein, or icv. The same iv cannula was used to administer
treatments and to sample blood. The delivery of iv treatments was
followed by flushing the cannula with 0.2–0.3 ml heparinized saline,
which ensures that they reach the jugular vein. HCG was purchased from
Sigma Corp. (St. Louis, MO) and dissolved in physiological saline. It
was injected iv at 1 U/kg, a dose that produces a submaximum T response
(C. Rivier, unpublished). The GnRH antagonist Azaline B (27), CRF, the
CRF-related peptide urocortin (UCN) (28), and the CRF antagonist
astressin (29) were synthesized by solid-phase methodology (30) and
generously provided by Dr. Jean Rivier (The Salk Institute). These
peptides were dissolved in apyrogenic water and artificial CSF. The
cyclooxygenase pathway inhibitor ibuprofen
(-methyl-4-[2-methyl-propyl]benzeneacetic acid; sodium salt),
prazosin (a specific 1-adrenergic antagonist),
phentolamine hydrochloride and phenoxybenzamine (general -adrenergic
antagonists), dl-propranolol hydrochloride (a general ß-adrenergic
antagonist), [-]-norepinephrine and l-isoproterenol (a specific
ß-adrenergic agonist) were purchased from Sigma Corporation. All
compounds were directly dissolved in apyrogenic saline (systemic
injections) or endotoxin-free artificial CSF (icv injections) except
prazosin, which was first dissolved in a small amount of alcohol that
did not interfere with testicular function. Doses were chosen on the
basis of published information (31, 32, 33, 34, 35, 36, 37, 38, 39), though we often tested them
over a wider range (see Results).
Hormones assay
Plasma T was measured by RIA in duplicates of unextracted plasma
(50 µl), as previously described (3). The ED20,
ED50, and ED80 are, respectively, 12.08 ±
1.15, 1.76 ± 1.84, and 0.26 ± 0.04 ng T/ml. In our
laboratory, the intra- and intercoefficients of variation for this
assay are 2.1% and 4%, respectively. The T antibodies show the
following cross-reactivities, calculated on a weight-per-weight basis
at approximately 50% binding: 5-dihydrotestosterone, 3.4%;
4-estren-17-ol-3-one, 20%; 11-ketotestosterone, 16%;
11ß-hydroxytestosterone, 1.2%.
Lesions of the VMH
Bilateral electrolytic lesions of the VMH were made 6–8 days
before experimentation in animals anesthetized with a mixture of
ketamine, xylazine, and acepromazine (see above). Stereotaxic
coordinates derived from the atlas of Paxinos and Watson (40) provided
information regarding the placement of the electrodes (anteroposterior,
-2.6 mm; lateral, ± 0.7 mm; dorsoventral, 9.2 mm). After the
electrodes (A-M Systems, Allied Electronics, San Diego, CA; no. 5765)
had been lowered, a current (7.5 mA) was delivered for 30–40 sec. Sham
operations were performed by lowering the electrodes at the same
posterior/lateral coordinates with no current passed through. Surgeries
were confirmed histologically in paraformaldehyde-fixed sections, which
were cut frozen at 30–60 µm and mounted on gelatin-coated slides.
Thionin-stained sections were examined under a microscope, and only
those animals with complete bilateral VMH lesions were included in the
statistical analysis of the data. All animals with appropriate VMH
lesions showed the expected (41) increase in food intake and body
weight gain (not shown).
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. P < 0.05 or below was
considered statistically significant.
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Results |
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).
Ibuprofen (10 mg/kg), which did not, in itself, alter the stimulatory
influence of hCG, modestly but significantly (P <
0.05) reversed the inhibitory effect of IL-1ß.
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). Though all peptide doses produced
significant (P < 0.05–0.01) responses, the most
striking responses were observed after administration of the highest
doses, which are illustrated in Fig. 2. We had shown that the effect of
icv IL-1ß is not mediated through decreases in LH levels (3). To
establish the fact that similarly, CRF, and UCN did not interfere with
testicular secretory activity by decreasing LH release, the experiments
were repeated in rats pretreated with the potent GnRH antagonist
Azaline B (50 µg/kg iv, 60 min before icv treatments), a dose shown
earlier not to interfere with hCG-induced T secretion or the inhibitory
influence of icv IL-1ß (3). The lack of importance of LH in mediating
the effect of CRF and UCN on T secretion was demonstrated by the
observation that these peptides were equally effective in rats in which
LH secretion had been totally blocked (not shown).
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, we therefore combined
values measured in vehicle- or astressin-injected animals. The T
response to hCG was significantly (P < 0.01) decreased
by IL-1ß, injected 60 min earlier. Blockade of central CRF receptors
did not reverse this effect (Fig. 3). Similar results were obtained
with other CRF antagonists, such as -hel CRF(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41) (42)
or [DPhe12,
Nle21,38]r/hCRF(12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41) (43), at doses up to
50 µg (not shown). As these antagonists differentially target CRF
receptor types 1 or 2 (28, 44, 45), our results suggest that within the
confines of our experimental protocol, no presently characterized CRF
receptors seem to mediate the effect of icv IL-1ß.
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- or ß-adrenergic receptors on the
inhibitory effect of IL-1ß, the iv injection of propranolol
was compatible with an intact testicular responsiveness. In contrast,
the systemic administration of prazosin or phenoxybenzamine
significantly prevented this response, a result that supports the
importance of catecholaminergic innervation in maintaining testicular
responsiveness to gonadotropins (12, 13) and further indicates that
this control primarily relies on -adrenergic receptors. These data
indicated that the experimental approach we had used was not feasible,
at least with regard to blockade of -adrenergic receptors. In a
second series of experiments, the rats were therefore injected with the
adrenergic antagonists icv. In these studies, one icv cannulae was used
to inject the vehicle or an antagonist, and the other icv cannula was
used to administer the vehicle or IL-1ß. Icv doses of antagonists
were chosen on the basis of published information indicating that at
least the highest concentration we used completely blocked the
corresponding adrenergic receptors (34, 36, 37). These reagents were
injected 20–30 min before IL-1ß, followed 60 min later by hCG (1
U/kg). The icv injection of 25 µg phenoxybenzamine or prazosin, which
in themselves did not alter the release of T induced by hCG, did not
significantly (P > 0.05) reverse the effect of icv
IL-1ß (Fig. 5). Higher doses of these
antagonists interfered with the T response to hCG, probably because
they leaked to the periphery (46, 47, 48) and, therefore, could not be
tested against IL-1ß. In contrast, the central administration of up
to 100 µg propranolol did not interfere with the stimulatory effect
of hCG on T release but significantly (P < 0.01),
though not totally, reversed the effect of icv IL-1ß (Fig. 6). In subsequent experiments not
illustrated here, we observed that propranolol also significantly
(P < 0.01) reversed the inhibitory effect of IL-1ß
when this cytokine was injected 5 min before hCG.
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, 3, and 4), was already
significant (P < 0.01) (Fig. 7A). The icv injection of 2 µg
isoproterenol (9.9 nmol) similarly induced a profound decrease in the T
response to hCG, whereas 10 µg (49.5 nmol) completely abolished it
(Fig. 7B). Though also capable of reducing the ability of the testes to
release T, norepinephrine was less potent than isoproterenol on a molar
basis, as it did not totally prevent the T response to hCG when
administered at 50 µg (54 nmol) (Fig. 7C). In contrast, the iv
injection of corresponding doses of either - or ß-adrenergic
agonists did not significantly interfere with hCG-induced T release
(not shown).
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). HCG (1 U/kg) induced the expected
significant (P < 0.01) rise in plasma T levels in both
groups of rats (Fig. 9). Prior treatment
(-60 min) with IL-1ß (80 ng) significantly (P <
0.01) decreased this response in both sham-operated and VMH-lesioned
rats, with no statistical differences between the two groups.
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Discussion |
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If neural connections between the hypothalamus and the testes exist and are important for the inhibitory effect of icv IL-1ß on T secretion, where do these fibers originate, and how does IL-1ß stimulate them? We first thought that such fibers might originate in the VMH, because in the female rat, this is the area from which ovarian connections that are important for sex steroid release arise (26). Our findings, however, suggest that this is apparently not the case in the male rat, because lesions of the VMH did not alter the inhibitory effect of icv IL-1ß. Systematic lesioning of brain areas of potential importance in our paradigm will thus be necessary to identify the origin of the brain-testicular pathway for which we believe there is evidence. In the meantime, we turned to another approach and used specific antagonists to explore the mechanisms through which icv IL-1ß decreases testicular secretory activity. We first considered the potential role of cyclooxygenase-dependent pathways, and we found that prostaglandins seem to play a significant, though modest, role in the inhibitory effect of IL-1ß. Because prostaglandins have usually been found to represent essential mediators of most of the biological effects exerted by proinflammatory cytokines (see Refs. 1, 17), it was somewhat surprising to observe that such was not the case in our model. We then considered the role of CRF, because the brain concentrations of this peptide are increased by IL-1ß (18, 19, 21, 22) and because it is a potent inhibitor of reproductive functions through centrally-mediated mechanisms (1). The validity of this concept was initially reinforced by the observation that the icv injection of CRF or UCN also decreased hCG-induced T secretion,. However, none of our attempts to block central CRF receptors, whether of type 1 or 2, were successful in reversing the influence of IL-1ß.
We then reasoned that if both IL-1ß and CRF decreased testicular
activity independently of the pituitary, but if the cytokine did not
seem to depend on CRF to do so, this meant that the activity of these
two compounds might depend on the release of a common intermediate.
Because both icv IL-1ß and CRF stimulate adrenergic activity in the
brain (21, 23, 24, 25, 49, 50, 51), we thought that activation of
catecholaminergic pathways might represent a reasonable mechanism.
This hypothesis was tested by administering adrenergic
antagonists before icv IL-1ß. Because we focused on compounds that
readily cross the blood-brain barrier, we first thought that we could
rely on the systemic injection of prazosin, phentolamine, or
phentoxybenzamine (which block -adrenergic receptors) or of
propranolol (which blocks ß-adrenergic receptors). We show here that
iv-injected -adrenergic antagonists completely abolished
the ability of hCG to release T. In contrast, very high doses of
propranolol were necessary to achieve even a modest reduction in the T
response. In the female rat, the electrical stimulation of the superior
ovarian nerve reduces progesterone release (52). The finding that the
-receptor antagonist phentolamine, but not the ß-receptor
antagonist l-propranolol, reversed this effect, prompted the authors of
this work to propose that the neural control of ovarian steroidogenesis
is excitatory through the stimulation of ß-adrenergic receptors, and
inhibitory through the stimulation of -receptors. Similarly, our
data suggest that in male rats, Leydig cells activity is under the
primary control of -adrenergic pathways. On the other hand, our
finding that systemic doses of l-propranolol, considered capable of
fully blocking ß-adrenergic receptors (39, 53), did not significantly
alter the stimulatory effect of hCG, was somewhat surprising because in
the male rat, the influence exerted by ß-adrenergic agonists on T
production is usually considered as facilitatory (10).
In view of the direct inhibitory influence of some adrenergic
antagonists, administered systemically, on testicular responsiveness to
hCG, we therefore decided to inject these compounds centrally. We show
here that blockade of central ß-adrenergic receptors produced a
significant, though not total, reversal of the inhibitory effect of icv
IL-1ß. These findings suggested that central administration of the
cytokine altered testicular secretory activity by stimulating
adrenergic fibers. To further substantiate this hypothesis, we
determined whether the icv injection of isoproterenol mimicked the
influence of IL-1ß, and we found that indeed this was the case. The
investigation of the influence of -adrenergic receptors, on the
other hand, was hindered by the fact that the central injection of the
corresponding antagonist itself interfered with testicular
responsiveness (which is not the case for ß-adrenergic antagonists).
Because phentolamine and phenoxybenzamine directly inhibit Leydig
activity (see Refs. 10, 54 for discussion), it is probable that when
injected icv, these reagents leaked to the periphery (46, 47, 48) and
therefore compromised T secretion through this mechanism. At present,
the contribution of -adrenergic pathways in our paradigm therefore
remains to be established, and studies of rats with
6-hydroxydopamine-induced lesions of discrete brain noradrenergic
circuits may help determine the overall importance of
catecholamines.
In conclusion, we have extended our previous finding that icv-injected IL-1ß decreases the T response to hCG (3), to show that a number of secretagogues participate in this response. Though prostaglandins and opiates may play some role (55), by far the most important influence yet described seems to be that of adrenergic pathways. Thus, though the influence exerted by peripheral ß-adrenergic agonists is usually facilitatory on T production (10), the opposite seems to be the case, with regard to the central influence of these compounds. One might argue that because the icv injection of IL-1ß blocks LH secretion, the fact that it also decreases T levels through a mechanism independent of LH is not particularly interesting. In our view, however, the finding that the inhibitory effect of IL-1ß on testicular responsiveness to hCG depends in part on the activation of ß-adrenergic pathways suggests that other stimuli that lower T levels may do so by up-regulating catecholamine production in the brain. It is well known that noxious signals, such as short-term restraint or alcohol administration, decrease T concentrations, in the absence of measurable changes in LH secretion (56, 57, 58, 59). Various mechanisms have been invoked to explain this apparent discrepancy, such as a testicular influence of the opiates released during stress (60), or a direct effect of alcohol on steroidogenesis (61, 62, 63). We propose that an additional (and not mutually exclusive) mechanism may be that of increased catecholaminergic neurotransmission in the brain. If proved to be correct, this hypothesis will provide a novel way in which a variety of homeostatic threats interfere with reproductive functions.
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Acknowledgments |
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Footnotes |
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Received December 9, 1997.
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References |
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receptors. J Androl 15:302–308This article has been cited by other articles:
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M. Herman and C. Rivier Activation of a Neural Brain-Testicular Pathway Rapidly Lowers Leydig Cell Levels of the Steroidogenic Acute Regulatory Protein and the Peripheral-Type Benzodiazepine Receptor while Increasing Levels of Neuronal Nitric Oxide Synthase Endocrinology, January 1, 2006; 147(1): 624 - 633. [Abstract] [Full Text] [PDF]
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S. Lee and C. Rivier Role Played by Hypothalamic Nuclear Factor-{kappa}B in Alcohol-Mediated Activation of the Rat Hypothalamic-Pituitary-Adrenal Axis Endocrinology, April 1, 2005; 146(4): 2006 - 2014. [Abstract] [Full Text] [PDF]
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D. R. Simorangkir, S. Ramaswamy, G. R. Marshall, and T. M. Plant In the Adult Male Rhesus Monkey (Macaca mulatta), Unilateral Orchidectomy in the Face of Unchanging Gonadotropin Stimulation Results in Partial Compensation of Testosterone Secretion by the Remaining Testis Endocrinology, November 1, 2004; 145(11): 5115 - 5120. [Abstract] [Full Text] [PDF]
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, 10 mg/kg),
injected iv 15–20 min before IL-1ß (80 ng, icv), partially reverses
the inhibitory effect of this cytokine on testicular responsiveness.
HCG was administered iv, 60 min after IL-1ß (
) or its vehicle
(•). In this and all subsequent figures, the gonadotropin was
injected immediately after obtention of the time zero blood. Each
point represents the mean ± SEM of
five to six rats. X, icv/iv vehicle. Because the T response to hCG was
statistically comparable, regardless of whether the animals had been
pretreated with the vehicle or ibuprofen, data of these two groups were
combined. **, P < 0.01 from icv vehicle + hCG; a,
P < 0.05 from icv IL-1ß + hCG.
, icv astressin/icv
IL-1ß/hCG; **, P < 0.01 from hCG alone.
, 4 mg/kg), on the T response to hCG (1 U/kg). (
, icv 25 µg
prazosin/IL-1ß/hCG, 
, antagonists/hCG, **, P
< 0.01 from icv vehicle/hCG.
, icv 50 µg propranolol/IL-1ß/hCG; 
