Brain Research Bulletin, Vol. 58, No. 4, pp. 405–409, 2002
Copyright © 2002 Elsevier Science Inc. All rights reserved.
0361-9230/02/$–see front matter
Effects of interleukin-1β on the steroid-induced
luteinizing hormone surge: Role of norepinephrine
in the medial preoptic area
Sheba M. J. MohanKumar∗and P. S. MohanKumar
Neuroendocrine Research Laboratory, Department of Pathobiology and Diagnostic Investigation,
College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
[Received 8 March 2002; Revised 3 May 2002; Accepted 6 May 2002]
ABSTRACT: Interleukin-1β (IL-1β), a cytokine, is known to
inhibit the preovulatory surge of luteinizing hormone (LH); how-
ever, the mechanism by which it does so is unclear. This study
was done to see if this effect is mediated through hypothala-
mic catecholamines. Adult female Sprague–Dawley rats were
ovariectomized and implanted with a push–pull cannula in the
medial preoptic area (MPA) of the hypothalamus. They were
injected subcutaneously with 30µg of Estradiol on the day
8 after surgery and with 2mg of Progesterone on day 10 at
1000h. On the day of perfusion (day 10), the rats were injected
with IL-1β or its vehicle at 1300h. Perfusate samples from the
MPA and blood samples from a jugular catheter were collected
from 1300 to 1800h. Catecholamine concentrations in the
perfusate were measured using high performance liquid chro-
matography (HPLC)-EC and LH levels in the serum using RIA.
Norepinephrine release in the MPA of control rats increased
significantly at 1530, 1600, and 1630h paralelling an increase in
LH at 1600h. In contrast, IL-1β treatment blocked the LH surge
and the rise in norepinephrine release in the MPA. No changes
were observed in dopamine release, both in control and
IL-treated animals. These results demonstrate for the first time
that IL-induced suppression of the LH surge is probably medi-
ated through inhibition of norepinephrine release in the MPA.
© 2002 Elsevier Science Inc. All rights reserved.
KEY WORDS: Hypothalamus, Neurotransmitters, Cytokines,
Neuroendocrine regulation, HPLC-EC.
Infection and disease processes are known to produce changes
in the central nervous system and the neuroendocrine system 
and there is a bidirectional connection between these two systems
and the immune system . One of the pronounced effects of in-
fection on the neuroendocrine system is the suppression of the
hypothalamo–pituitary–gonadal (HPG) axis [1,3]. Interleukin-1β
(IL-1β), a cytokine, is known to be an important mediator of this
effect. IL-1 has been shown to suppress LH levels in castrated
male rats . It also inhibits the preovulatory luteinizing hormone
(LH) surge and ovulation during the afternoon of proestrus in
intact female rats  and blocks the steroid-induced LH surge in
ovariectomized animals [6,7]. While the mechanisms involved are
still unclear, evidence points to the hypothalamus as being the main
site of action [5–7].
In the rat, luteinizing hormone releasing hormone (LHRH)
neurons that regulate the LH surge are localized in specific areas
of the hypothalamus such as the suprachiasmatic nucleus, medial
preoptic area (MPA), and the arcuate nucleus. Of these, the MPA
has the largest number of LHRH perikarya . These neurons
are influenced by a wide variety of neurochemicals [9,10]. Of
these, the catecholamines, norepinephrine (NE), and dopamine
(DA) have been the most widely studied [8,11]. The activity of
catecholamine synthesizing enzymes in the MPA is known to
change paralleling LH levels during different stages of the es-
trous cycle [12,13]. Moreover, NE concentration, turnover, and
release increase significantly in the MPA during the afternoon of
proestrus at the time of preovulatory LH surge [14–18]. Thus, it
is possible that IL-1’s effects on LH secretion may involve cen-
tral noradrenergic systems, especially NE levels in the MPA. The
present study was, therefore, done to examine the role of both
NE and DA levels in the MPA in the IL-induced inhibition of the
LH surge. For this purpose, push–pull perfusion in combination
with high performance liquid chromatography (HPLC) was used
to obtain catecholamine release profiles in the MPA before, dur-
ing, and after the LH surge in ovariectomized steroid-primed rats.
Concurrent sampling of blood from a jugular catheter was used to
measure simultaneous changes in LH levels in the periphery.
MATERIALS AND METHODS
Three- to four-month-old female Sprague–Dawley rats were
used in the experiments. They were housed in light-controlled
(lights on from 0500 to 1900h) and air-conditioned (23 ± 2◦C)
animal rooms and were given rat chow and water ad lib.
Push–Pull Cannula Implantation and Ovariectomy
The animals were weighed and randomly divided into two
groups. All animals were bilaterally ovariectomized and were im-
planted with a push–pull cannula in the MPA as described before
∗Address for correspondence: Dr. Sheba M.J. MohanKumar, Neuroendocrine Research Laboratory, Department of Pathobiology and Diagnostic
Investigation, A 522 E. Fee Hall, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA. Tel.: +1-517-432-4680;
Fax: +1-517-432-7480; E-mail: firstname.lastname@example.org
406 MOHANKUMAR AND MOHANKUMAR
. Briefly, the animals were given Atropine sulphate (2.2mg/kg,
intraperitoneal (i.p.)) to reduce salivary secretions and to keep the
airways open and were anesthetized using sodium pentobarbital
(50mg/kg, i.p.). The ovaries were removed through a midventral
incision after ligation of the uterine horns and the surrounding vas-
culature. The abdominal muscles were sutured using sterile cotton
sutures and the skin incision was closed using sterile autoclips.
Immediately after ovariectomy, the rats were implanted with a
push–pull cannula in the MPA using a stereotaxic apparatus (Kopf,
Tujunga, CA). Construction of the push–pull cannula has been de-
scribed previously . It consisted of an 8.5mm-long outer can-
nula made from a 22-ga hypodermic needle. The coordinates used
for implantation of the cannula were 8.5mm ventral, 0.3mm pos-
terior, and 0.3mm lateral to the bregma . The cannula was
secured in place with screws and dental cement. After implanta-
tion, a 29ga stainless steel stylet was introduced so that it extended
0.5mm beyond the tip of the outer cannula. Rats were housed indi-
vidually in flat-bottomed cages after recovery. They were periodi-
cally monitored for signs of infection or discomfort and were used
in the experiments 8 days after surgery. Rats that showed any sign
of infection were excluded from the study. All procedures involv-
ing animals were approved by the Institutional animal care and use
We followed the steroid treatment protocol used by Kalra et al.
. On the day 8 after surgery, rats in both groups were treated with
a subcutaneous (s.c.) injection of estrogen (30µg in 0.1ml corn
oil) at 1000h. On the day 9, they were implanted with indwelling
catheters in the jugular vein as described previously . On the
day 10, the rats received an s.c. injection of 2mg of progesterone
in 0.1ml of corn oil at 1000h and were subjected to push–pull
Push–Pull Perfusion Procedure
Push–pull perfusion was performed as described earlier
[14,19,21,22]. On the day of push–pull perfusion, the stylet was
replaced with an inner cannula assembly, which consisted of two
29-ga stainless steel tubes of unequal lengths. The longer tube
(3.5cm), which protruded 0.5mm beyond the outer cannula, was
used to introduce (push) the perfusion medium at the implantation
site. The shorter tube (2.0cm) was used to collect (pull) perfusate
from the implantation site. The two tubes were kept together in a
2mm-long piece of Silastic tubing which was mounted with epoxy
resin in the lower part of a tuberculin syringe cut at the 0.05ml
mark. The push and pull tubes were connected to two identi-
cally calibrated peristaltic pumps (Pharmacia, Uppsala, Sweden).
Before starting the perfusion, care was taken to make sure that
the pumps were perfectly balanced. Artificial cerebrospinal fluid
(ACSF) was used as the perfusion medium. It consisted of CaCl2
(0.087g/l), NaCl (7.188g/l), KCl (0.358g/l), MgSO4(0.296g/l),
and Na2HPO4(1.703g/l) and had a pH of 7.3. Pump speeds were
adjusted to achieve a flow rate of 10µl/min.
The rats were introduced into the perfusion cages at 1000h
and perfusion was started at 1200h. Animals in the control group
(n = 7) were injected intraperitoneally with 250µl of PBS-0.1%
BSA at 1300h while animals in the experimental group (n = 8)
were treated with 5µg of human recombinant IL-1β in 250µl
of PBS-0.1% BSA. Push–pull perfusates were collected in both
groups from 1300 to 1800h at 30-min intervals at the rate of
10µl/min. Perfusates were mixed with 0.5M HClO4at the rate of
25:1 v/v and stored at −70◦C until HPLC analysis.
Venous blood was collected through the jugular catheter at 1-h
intervals from 1300 to 1800h. Blood was replaced by an equal
volume of heparinized saline containing 10 units of heparin per
centrifuged at 2000rpm for 20min to separate the serum. Serum
samples were stored at −20◦C until they were used for LH-RIA.
After completion of perfusion, the animals were sacrificed, and
the brains were immediately removed and frozen. The perfusion
which were obtained using a cryostat (Slee, London, UK) main-
tained at −10◦C and stained with cresyl violet.
The HPLC-EC system has been described before [13–15,19,21,
23]. Briefly, it consisted of an LC-4B amperometric detector
(Bioanalytical Systems, West Lafayette, IN, USA), a glassy car-
bon working electrode, a phase II, 5µm ODS reverse phase,
75mm × 3.2mm, C-18 column, and a C-R6A Chromatopac in-
tegrator (Shimadzu, Columbia, MD, USA). The mobile phase
consisted of monochloroacetic acid (14.5g/l), sodium hydroxide
(4.675g/l), octanesulfonic acid disodium salt (0.3g/l), ethylene-
diaminetetraacetic acid (0.25g/l), and acetonitrile (35ml/l) in
pyrogen-free, degassed water, filtered through a Milli-Q purifica-
tion system (Millipore Co., Bedford, MA, USA). The pH of the
mobile phase was adjusted to 3.1 using NaOH. The flow rate of
the pump (Shimadzu LC-6A) was 1.1ml/min. The sensitivity of
the detector was 1.0nA full scale, and the potential of the working
electrode was 0.65V. The column and the working electrode were
kept in a Shimadzu CTO-6A oven at a temperature of 37◦C. At
the time of HPLC-EC analysis, the samples were thawed at 60◦C
for 1min. A mixture of 75µl of the sample and 25µl of the in-
ternal standard (0.05M isoproterenol) was injected into the HPLC
system. Neurotransmitter release was expressed as picogram per
A double antibody RIA was used to determine LH levels in the
serum samples as described before . LH label was obtained
from Hazelton Washington (Vienna, VA) and the LH standards and
antibody were obtained from NIDDK. The reference preparation
for LH was NIDDK rLH-RP-3. The first antibody used was anti
rLH-S11. One hundred microliters of the serum samples were as-
sayed in duplicate. The assay had a sensitivity of less than 10pg
and an interassay variability of 5.26 ± 1.06% and an intraassay
variability of 6.89 ± 1.7%.
The differences in the profiles of NE and DA release and LH
levels in the serum during the entire observation period were an-
alyzed using repeated measures ANOVA followed by post hoc
Fisher’s LSD test.
Location of the Push–Pull Cannulae
Fig. 1 depicts the locations of the push–pull cannulae in the two
groups of animals. Histological examination revealed that the tips
of the push–pull cannulae in all the animals were in the MPA. The
area of perfusion around each cannula tip was about 0.5mm.
Effects of IL-1β on NE Release
NE release in control animals that were treated with PBS-BSA
and experimental animals that were treated with 5µg of hrIL-1β
are shown in Fig. 2A. NE levels (pg/min, mean ± SE) in the con-
trol animals were 8.1 ± 2.0 at 1300h and increased gradually to
EFFECTS OF INTERLEUKIN-1β ON THE STEROID-INDUCED LUTEINIZING HORMONE SURGE 407
Fig. 1. Schematic representation of the sagittal section of a rat brain indicat-
ing the locations of the push–pull cannulae in (ovx+EP+vehicle)-treated
group (?; n = 7) and in (ovx + EP + IL)-treated group (?; n = 8). The
numbers A1–P3 represent coronal plates extending 1mm anterior (A1)
to 3mm posterior (P3) from the bregma (AP0). MPA = medial preop-
tic area, SCh = suprachiasmatic nucleus, AH = anterior hypothalamus,
LA = lateroanterior hypothalamic nucleus, AVPO = anteroventral preop-
tic nucleus, MPO = median preoptic nucleus, StHy = striohypothalamic
nucleus, VMH = ventromedial hypothalamus, OX = optic chiasm, and
SOX = supraoptic decussation. The location of the push–pull cannula in
individual animals was determined by examining stained serial brain sec-
tions under a light microscope.
11.7 ± 2.7 at 1530h and reached a peak at 1630h (13.2 ± 3.4,
p < 0.05) before declining to basal levels. In contrast, treatment
with 5µg of IL-1β completely blocked the rise in NE release. NE
levels in these animals were 5.0 ± 2.1 at 1300h and remained at
about the same level during the rest of the period of observation.
There were differences in the basal levels, the timing of the peaks,
and the amplitude of the peaks but the consistent feature observed
in all the control animals was the persistent and progressive in-
crease in NE release at the time of the LH surge. In contrast to the
control animals, NE release and LH levels in the IL-treated ani-
mals remained low and were free of any significant change during
the entire period of observation.
Effects of IL-1β on LH
Serum LH levels (ng/ml, mean ± SE; Fig. 2B) in the control
animals were 0.3 ± 0.2 at 1300h and increased progressively to
reach a peak at 1600h (15.9 ± 7.3, p < 0.05) before declining to
basal levels at 1800h (0.6±0.3). A distinct LH peak was observed
in all the control animals. In contrast, treatment with IL-1β blocked
the increase in LH observed in the control animals. In the IL-treated
animals, LH was 0.27 ± 0.1 at 1300h and remained at that level
during the rest of the period of observation. LH levels were free
of any change in five out of eight animals. Two animals showed a
modest peak in LH at 1600h.
Effects of IL-1β on DA
In contrast to NE, DA release profiles in individual animals, in
both the control and IL-treated groups, remained unchanged during
the entire observation period. There was no significant difference
in DA release (pg/min, mean ± SE) between control and experi-
mental animals (Fig. 2C). DA levels at 1300h were 4.5±1.8 in the
control group and 3.4±1.4 in the IL-1-treated group. It remained
at about that level in both the groups throughout the entire period
Fig. 2. The effects of IL-1β on NE and DA release in the medial preoptic
area and LH levels in the serum. Average (mean±SE) NE release (pg/min)
profile in the medial preoptic area measured at 30-min intervals in ovariec-
tomized estrogen and progesterone-treated animals that were either treated
with 5µg of IL-1β (n = 8) or the vehicle (n = 7) for IL-1β,∗p < 0.05
(A). Average (mean±SE) LH (ng/ml) profile measured at hourly intervals
from 1300 to 1800h in ovariectomized estrogen and progesterone-treated
animals that were either treated with 5µg of IL-1β or the vehicle for
IL-1β,∗p < 0.05 (B). Average (mean ± SE) DA release (pg/min) profile
in the medial preoptic area measured at 30-min intervals in ovariectomized
estrogen and progesterone-treated animals that were either treated with
5µg of IL-1β or the vehicle for IL-1β (C).
Results from this study provide evidence for the first time
that IL-1-induced suppression of LH may be mediated through
changes in central noradrenergic activity. NE release in the MPA
increased significantly during the afternoon, paralleling an in-
408MOHANKUMAR AND MOHANKUMAR
crease in LH in control ovariectomized steroid-primed rats. In-
traperitoneal injection of 5µg of IL-1β blocked the rise in NE
levels in the MPA and completely suppressed the LH surge in five
out of eight animals. This indicates that IL-1β probably blocks
the LH surge in ovariectomized steroid-primed rats by decreasing
NE release in the MPA. In contrast to NE, DA probably plays
little or no role in the LH surge observed in ovariectomized
steroid-primed rats since DA release remained essentially free of
change during the entire period of observation in control animals.
Systemic administration of IL-1 did not affect DA release either.
These results also indicate that the effects of IL-1β are highly
specific affecting one catecholamine in a specific brain area while
leaving another untouched. This implies that IL-1 is capable
of influencing different catecholaminergic neurons in different
ways. This is supported by another study in which IL-1β was
shown to affect catecholamines and indoleamines differentially
depending on the area of the hypothalamus that was involved
In the present study, we focussed on the MPA because it is rich
in LHRH cell bodies and is part of the preopticosuprachiasmatic
tuberoinfundibular system of LHRH neurons . It is believed to
be a critical area where NE acts to regulate LH release. Increases in
NE content, concentration, turnover, and release during the after-
noon of proestrus have been reported in the MPA [11,14,15,17,18].
Also, the activity of tyrosine hydroxylase (TH), the rate-limiting
enzyme in the synthesis of catecholamines, has been reported to
increase in the MPA during the afternoon of proestrus . The
MPA receives its noradrenergic innervation from the brain stem
[8,10]. Recent studies involving the use of noradrenergic deple-
tors and lesioning of the noradrenergic brain stem nuclei have
produced decreases in NE content and LHRH mRNA levels in
the MPA and this caused the suppression of pulsatile LH secre-
tion [24,25]. All these support findings from the present study in
which we observe increases in NE release in the MPA at the time
of LH surge in ovariectomized, steroid-primed rats (control). The
interesting finding in this study was that IL-1β blocked the rise
in NE release in the MPA and simultaneously suppressed the LH
surge. These results demonstrate for the first time that this could
probably be one of the mechanisms by which IL-1 suppresses LH
The mechanism by which IL-1 suppresses the steroid-induced
release of NE in the MPA in ovariectomized animals is not clear. It
is possible that IL-1 could act at the level of noradrenergic termi-
nals in the MPA to inhibit NE release. This would require a local
increase in the level of IL-1 in the MPA. In fact, a recent study
has shown that IL-1β mRNA levels increased in the MPA, when
animals were subjected to chronic stress. A more interesting obser-
vation in this study was that this was accompanied by a reduction
in LHRH mRNA in this area . Another possible site of action
could be the A1 and A2 brain stem noradrenergic regions, which
provide noradrenergic innervation to the MPA . It is possible
that IL-1 could act at the level of these nuclei to inhibit NE release
in the MPA. These regions are also activated when animals are in-
jected intraperitoneally with IL-1 or lipopolysaccharide [27–29].
The exact mechanism by which this could transduce to a decrease
in NE release in the MPA needs to be examined.
The decrease in LH levels associated with IL-1 administration
may involve other neurochemicals as well. Previous studies
have shown that the inhibitory effect of IL-1 on basal go-
nadotropin secretion can be reversed by the administration of
corticotropin-releasing hormone (CRH) antibodies suggesting the
involvement of CRH in this sequence of events . Nalox-
one, a potent opioid antagonist has been shown to overturn the
IL-1-induced suppression of the LH surge in ovariectomized
steroid-primed rats indicating a role for endogenous opioids in this
phenomenon . Other neurochemicals, such as prostaglandins,
nitric oxide, excitatory amino acids, neuropeptide Y, and gamma
amino butyric acid, may also be involved in the IL-1-induced
suppression of LH release [3,28,31–35]. The long list of substances
that may contribute to this phenomenon is not surprising because
the regulation of LH secretion is complex in nature involving a
host of neurochemicals [8,10,11].
Unlike NE, the role of DA in LH regulation is not understood
clearly [8,10,11]. Recent studies measuring DA release in the MPA
and the medial basal hypothalamus have discounted the possibility
that DA might have a stimulatory role in LH surge [14,22]. In these
studies, DA release either did not change or decreased marginally
during the afternoon of proestrus indicating that it either has an
inhibitory role or is probably not involved in the regulation of the
LH surge. The results from the present study support this conclu-
sion. These results are more convincing, since IL-1 was capable of
blocking the rise in NE release but left DA release unaffected. This
differential action of IL-1 is believed to contribute to its specific
effects on the neuroendocrine system .
The route of IL-1 administration has also been reported to
play a role in the suppression of LH secretion. When given in-
tracerebroventricularly, both IL-1α and -1β were able to inhibit
the LH surge in young cycling female rats. However, when given
peripherally, these cytokines were incapable of affecting LH secre-
tion. Central administration of IL-1 also interfered with ovulation
while systemic IL-1 did not [4–6]. However, in the present study,
i.p. administration of IL-1β blocked the LH surge and this effect
was accompanied by inhibition of NE release in the MPA. This
could be attributed to the dose of IL-1β used in the present study
(5µg) compared to doses ranging from 250ng to 1µg that were
used in the other studies. However, the dose of 5µg, we feel, is
not excessive since it did not completely suppress the LH surge in
three out of eight animals.
The routes by which IL-1 affect the brain to produce its cen-
tral effects are being studied. There is evidence to show that IL-1
can cross the blood-brain barrier . It may also bind to IL-1 re-
ceptors located on abdominal paraganglia of the vagus to activate
brain stem nuclei . It could even pass through regions where
the blood–brain barrier is weak and bind to its receptors that have
been identified in different parts of the brain [27,28]. In this pro-
cess, it could affect a variety of neurotransmitters that regulate LH
secretion. Results from the present study demonstrate for the first
time that NE could be a possible mediator of the IL-induced inhi-
bition of the LH surge.
This work was partially supported by the Grant NIH AG05980.
The authors thank Drs. Michael Widmer and Steven Gillis, Im-
munex Corporation, for the kind gift of IL-1β. The authors also
thank Mr. Shawn A. Taylor for his technical assistance.
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