ORIGINAL PAPER

Interleukin-1b (187–207)-Induced Hyperthermia is Inhibitedby Interleukin-1b (193–195) in Rats

Miklos Palotai • Edina Kiss • Zsolt Bagosi •

Miklos Jaszberenyi • Gabor Toth • Gyorgyi Varadi •

Gyula Telegdy

Received: 10 October 2013 / Revised: 26 November 2013 / Accepted: 30 November 2013 / Published online: 13 December 2013

� Springer Science+Business Media New York 2013

Abstract Interleukin-1b (IL-1b) is a pro-inflammatory

cytokine, which plays an important role in the immune

response and signal transduction both in the periphery and

the central nervous system (CNS). Various diseases of the

CNS, including neurodegenerative disorders, vascular

lesions, meningo-encephalitis or status epilepticus are

accompanied by elevated levels of IL-1b. Different

domains within the IL-lb protein are responsible for dis-

tinct functions. The IL-lb domain in position 208–240 has

pyrogenic properties, while the domain in position 193–

195 exerts anti-inflammatory effects. Previous studies

provide little evidence about the effect of the domain in

position 187–207 on the body temperature. Therefore, the

aim of the present study was to investigate the action of IL-

1b (187–207) and its interaction with IL-1b (193–195) on

the body temperature. IL fragments were administered

intracerebroventricularly and the body temperature was

measured rectally in male Wistar rats. IL-1b(187–207)

induced hyperthermia, while IL-1b (193–195) did not

influence the core temperature considerably. In co-admin-

istration, IL-1b (193–195) completely abolished the IL-1b(187–207)-induced hyperthermia. The non-steroid anti-

inflammatory drug metamizole also reversed completely

the action of IL-1b (187–207). Our results provide evi-

dence that the IL-lb domain in position 187–207 has

hyperthermic effect. This effect is mediated through pros-

taglandin E2 stimulation and other mechanisms may also

be involved in the action of IL-1b (187–207). It also sug-

gests that IL-lb domain in position 187–207 and IL-1b(193–195) fragment may serve as novel target for treatment

of disorders accompanied with hyperthermia.

Keywords IL-1b (187–207) � IL-1b (193–195) �Metamizole � Hyperthermia

Introduction

Interleukin-1b (IL-1b) was first described in the early 1940s

as an agent coming from rabbit peritoneal cells. Its first

biological property to be discovered was to produce fever,

and therefore was termed ‘‘pyrexin’’ or ‘‘endogenous pyro-

gen’’ [1]. IL-1b is a pro-inflammatory cytokine, which plays

an important role in the immune response and signal trans-

duction both in the periphery and the central nervous system

(CNS) [2, 3]. It is released during inflammatory processes

and neuropathic pain [4]. Intracerebroventricular (ICV)

administration of IL-1b produces hyperthermia, which is

mediated by the pre-optic anterior hypothalamus (PO/AH)

[5, 6]. Prostaglandin E2 (PGE2) has been thought to be the

mediator acting within the blood–brain barrier [6, 7]. It is

apparent that IL-1b is an important mediator in the cross-talk

between the nervous and immune systems, and also partic-

ipates in modulation of the nociceptive threshold [8].

Blockade of IL-1b reduces body temperature and pain.

ICV administration of a-melanophore-stimulating hormone

(a-MSH) inhibits the effects of IL-1b and this inhibition is

mediated by the arcuate nucleus (ARC) [5]. The tripeptide

M. Palotai � E. Kiss � Z. Bagosi � M. Jaszberenyi �G. Telegdy (&)

Department of Pathophysiology, Faculty of Medicine, University

of Szeged, 6725, Semmelweis Str. 1, Szeged, Hungary

e-mail: telegdy.gyula@med.u-szeged.hu

G. Toth � G. Varadi

Department of Medical Chemistry, Faculty of Medicine,

University of Szeged, Szeged, Hungary

G. Telegdy

Neuroscience Research Group of the Hungarian Academy

of Sciences, Szeged, Hungary

123

Neurochem Res (2014) 39:254–258

DOI 10.1007/s11064-013-1215-9

analogues of IL-1b, such as the C-terminal tripeptide of a-

MSH (Lys-D-Pro-Val) or the IL-1b (193–195) (Lys-D-Pro-

Thr) also exert antagonistic action on IL-1b [9, 10]. Effects

of IL-1b can also be ameliorated by non-steroidal anti-

inflammatory drugs (NSAIDs) [11].

Different domains within the IL-lb protein are respon-

sible for distinct functions. These biologically important

regions have been investigated by using fragments of the

IL-1b with agonist [12] and antagonist [10] properties. For

instance, IL-1b fragment (163–171) has immunostimula-

tory and adjuvant effects [13]. Additionally, IL-1b (208–

240) increases body temperature through PGE2 production

and has somnogenic activity [12]. Previous studies provide

little evidence about the effect of the IL-lb domain in

position 187–207 on the body temperature. Therefore, the

aim of the present study was to investigate the action of IL-

1b (187–207) and its interaction with IL-1b (193–195) on

the body temperature in rats. In the present study, IL-1b(187–207) was administered intracerebroventricularly

alone or in combination with IL-1b (193–195).

Methods

Animals

Male Wistar rats weighing 150–250 g were used in our

experiments. The animals were treated in accordance with

the instructions of the Ethical Committee for the Protection

of Animals in Research, University of Szeged, Hungary.

The rats were kept in their home cages at a constant tem-

perature on a standard illumination schedule with 12-h

light and 12-h dark periods (lights on from 6:00 a.m.).

Commercial food and tap water were available ad libitum.

To minimize the effects of nonspecific stress, the rats were

handled daily.

Surgery

For intracerebroventricular (ICV) administration, the rats

were implanted with a stainless steel Luer canulla (10 mm

long) aimed at the right lateral cerebral ventricle under

Nembutal (35 mg/kg, intraperitoneally, IP) anesthesia. The

stereotaxic coordinates were 0.2 mm posterior; 1.7 mm

lateral to the bregma; 3.7 mm deep from the dural surface,

according to the atlas of Pellegrino et al. 1979 [14]. Cannulas

were secured to the skull with dental cement and acrylate.

The rats were used after a recovery period of 5 days.

Chemicals

IL-1b (187-207) (Cys-Val-Leu-Lys-Asp–Asp-Lys-Pro-

Thr-Leu-Gln-Leu-Glu-Ser-Val-Asp-Pro-Lys-Asn-Tyr-Pro)

was synthesized at the Department of Medical Chemistry

(University of Szeged, Hungary) on an ABI 430 automatic

synthesizer, applying tert-butyloxycarbonyl (Boc) chemis-

try and dicyclohexylcarbodiimide (DCC) coupling with a

fourfold excess of reagents. 4-Methylbenzhydrylamine

(MBHA) resin was used as solid support. The peptide was

detached from the resin with the use of 8 % dimethyl

sulfide (DMS), 2 % anisole, 2 % cresol and 2 % p-thio-

cresol in liquid HF at -5 to 0 �C. The crude peptide was

purified by semipreparative reverse-phase high-perfor-

mance liquid chromatography (RP-HPLC) and the purity of

the peptide was characterized by analytical RP-HPLC. The

identity of the IL-1b (187–207) was verified by mass

spectrometry with a Finnigan TSQ 7000 tandem quadru-

pole mass spectrometer equipped with an electrospray ion

source. IL-1b (193–195) (Lys-D-Pro-Thr) was purchased

from Bachem Inc., Switzerland. Metamizole (Algopyrin)

was provided by Sanofi-Aventis Inc., Hungary.

Treatment

All the experiments were carried out between 8:00 and 10:00

a.m. First, to establish a dose–response curve, different doses

of IL-1b (187-207) (0.5, 1.0 lg) or IL-1b (193–195) (1.0,

2.0, 4.0 lg) were dissolved in saline in a volume of 2 ll and

were injected ICV into conscious rats. Control animals were

treated with 2 ll saline alone. Second, the most effective

dose of IL-1b (187–207) was selected and used in combi-

nation either with the most effective dose of IL-1b (193–195)

or with intraperitoneally (IP) administered metamizole

(50 mg/kg). IL fragments were administered at 0 min.

Metamizole was injected 30 min prior to the administration

of IL fragments. After the treatment, the rats were removed

from their home cages to measure the rectal temperatures.

Measurement of Rectal Temperatures

Rectal temperatures were measured at 0, 30, 60, 90, 120

and 180 min after the ICV administration of the IL frag-

ments with an electric thermocouple (Ellab Instruments,

Copenhagen, Denmark) inserted 2 cm into the rectum.

Statistical Analysis

Statistical analysis of the results was performed by repe-

ated measure analysis of variance (RMANOVA, Statistica

v5.0, StatSoft Inc.) followed by Tukey’s post hoc com-

parison test. Only the mean percentages were plotted and

the standard error of the mean (SEM) is given in the figure

captions. The differences between groups were examined

by Tukey’s post hoc comparison test, and a probability

level of 0.05 or less was accepted as indicating a statisti-

cally significant difference.

Neurochem Res (2014) 39:254–258 255

123

Results

The core temperature was elevated by IL-1b (187–207),

but not by IL-1b (193–195). ICV administration of 1.0 lg/

2.0 ll IL-1b (187–207) increased significantly the core

temperature from 30 to 180 min after the injection;

[F(2,15) = 0.89, p = 0.43 at 0 min; F(2,15) = 5.04,

p \ 0.05 at 30 min; F(2,15) = 9.85, p \ 0.05 at 60 min;

F(2,15) = 8.19, p \ 0.05 at 90 min; F(2,15) = 10.65,

p \ 0.05 at 120 min; F(2,15) = 5.58, p \ 0.05 at 180 min

for 1.0 lg/2.0 ll IL-1b (187–207) versus control] (Fig. 1).

The core temperature was not influenced considerably

by IL-1b (193–195). Although, significant effect was

observed with 1.0 lg/2.0 ll at 30 min [F(3,20) = 0.89;

p \ 0.05 for IL-1b (193–195) versus control] and 2.0 lg/

2.0 ll at 180 min [F(3,20) = 7.65; p \ 0.05 for IL-1b(193-195) versus control] (Fig. 2).

Intracerebroventricular administration of 2.0 lg/2.0 ll

IL-1b (193–195) antagonized completely the significant

effect of 1.0 lg/2.0 ll IL-1b (187–207) on core tempera-

ture [F(3,41) = 13.45, p \ 0.05 at 60 min; F(3,41) =

10.49, p \ 0.05 at 90 min; F(3,41) = 3.16, p \ 0.05 at

120 min for 1.0 lg/2.0 ll IL-1b (187–207) versus 2.0 lg/

2.0 ll IL-1b (193–195)] (Fig. 3).

Intraperitoneal administration of 50 mg/kg metamizole

reversed the significant effect of IL-1b (187–207) on core

temperature from 30 to 180 min after the ICV injection of

IL fragments [F(3,39) = 2.85, p = 0.059 at 0 min;

F(3,39) = 22.34, p \ 0.05 at 30 min; F(3,39) = 30.64,

p \ 0.05 at 60 min; F(3,39) = 19.31, p \ 0.05 at 90 min;

F(3,39) = 7.27, p \ 0.05 at 120 min; F(3,39) = 10.31,

p \ 0.05 at 180 min for 1.0 lg/2.0 ll IL-1b (187–207)

versus 1.0 lg/2.0 ll IL-1b (187–207) ? 50 mg/kg

metamizol]. Metamizole also decreased considerably the

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0 30 60 90 120 150 180

Co

re t

emp

erat

ure

(°C

)

Time (min)

control (6)

IL-1β (187-207) 0.5 µg/2µl (6)

IL-1β (187-207) 1.0 µg/2µl (6)

Fig. 1 The effect of interleukin-1b (187–207) on core temperature in

rat. Intracerebroventricular administration of 1.0 lg/2.0 ll IL-1b(187–207) increased significantly the core temperature from 30 to

180 min after the injection. 0.5 lg/2.0 ll IL-1b (187–207) did not

influence the core temperature significantly. IL-1b (187–207) was

injected at 0 min. The numbers in brackets indicate the number of

rats. Statistical analysis of the results was performed by repeated

measure analysis of variance (RMANOVA, Statistica v5.0, StatSoft

Inc.) followed by Tukey’s post hoc comparison test. *p \ 0.05

1.0 lg/2.0 ll IL-1b (187–207) versus control

35

36

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38

39

40

0 30 60 90 120 150 180

Co

re t

emp

erat

ure

(°C

)

Time (min)

control (6)IL-1β (193-195) 1.0 µg/2µl (6)IL-1β (193-195) 2.0 µg/2µl (6)IL-1β (193-195) 4.0 µg/2µl (6)

Fig. 2 The effect of interleukin-1b (193–195) on core temperature in

rat. Intracerebroventricular administration of IL-1b (193–195) has not

influenced the core temperature considerably. Although, significant

effects were observed with 1.0 lg/2.0 ll at 30 min and 2.0 lg/2.0 ll

at 180 min. IL-1b (193–195) was injected at 0 min. The numbers in

brackets indicate the number of rats. Statistical analysis of the results

was performed by repeated measure analysis of variance (RMANO-

VA, Statistica v5.0, StatSoft Inc.) followed by Tukey’s post hoc

comparison test. *p \ 0.05 1.0 lg/2.0 ll IL-1b (193–195) versus

control at 30 min; **p \ 0.05 2.0 lg/2.0 ll IL-1b (193–195) versus

control at 180 min

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39

40

0 30 60 90 120 150 180

Co

re t

emp

erat

ure

(°C

)

Time (min)

control (11)

IL-1β (187-207) 1.0 µg/2.0 µl (11)IL-1β (193-195) 2.0 µg/2.0 µl (11)IL-1β (187-207) 1.0 µg/2.0 µl + IL-1β (193-195) 2.0 µg/2.0 µl (12)

Fig. 3 Interleukin-1b (193–195) antagonizes the interleukin-1b(193–195)-induced hyperthermia. 2.0 lg/2.0 ll IL-1b (193–195)

antagonized the 1.0 lg/2.0 ll IL-1b (187–207)-induced hyperthermia

from 60 to 120 min after intracerebroventricular co-administration of

the fragments. IL fragments were injected at 0 min. The numbers in

brackets indicate the number of rats. Statistical analysis of the results

was performed by repeated measure analysis of variance (RMANO-

VA, Statistica v5.0, StatSoft Inc.) followed by Tukey’s post hoc

comparison test. *p \ 0.05 1.0 lg/2.0 ll IL-1b (187–207) ? 2.0 lg/

2.0 ll IL-1b (193–195) versus 1.0 lg/2.0 ll IL-1b (187–207)

256 Neurochem Res (2014) 39:254–258

123

core temperature of the control group from 30 to 90 min

[F(3,39) = 22.34, p \ 0.05 at 30 min; F(3,39) = 30.64,

p \ 0.05 at 60 min; F(3,39) = 19.31, p \ 0.05 at 90 min

for control versus control ? metamizole] (Fig. 4).

Discussion

IL-1b is a pro-inflammatory cytokine that participates in

several neuroimmunological and neurophysiological

activities. In the CNS, IL-1b is mainly produced by the

activated microglia following diverse forms of neuroin-

flammation and neurodegeneration [15]. In addition, IL-1bis an endogenous pyrogen and is involved in the develop-

ment of the hyperthermic response to exogenous pyrogens

[16]. Pro-inflammatory domains of IL-1b are localized

between the amino acids 163–171 [17] and 208–240 [12].

Our study provides evidence, that the IL-1b domain in

position 187–207 also have pyrogenic properties.

IL-1b has been shown to stimulate arachidonic acid

metabolism, the most consistently observed effect is the

increased production of PGE2 from various cell types

[18]. Fever, which is perhaps the most conspicuous

component of the acute phase of the immune response, is

thought to occur as a result of the actions of PGE2 on the

PO/AH. NSAIDs abolish the effects of IL-1b by inhibit-

ing the enzyme cyclo-oxygenase (COX) and consequently

preventing the biosynthesis of prostanoids from arachi-

donic acid [18]. Our results suggest that the non-steroidal

anti-inflammatory drug, metamizole can reverse the Il-1b(187–207)-induced hyperthermia. We presume that this

effect is mediated through PGE2, since the inhibition of

COX enzyme reversed the action of Il-1b (187–207).

Amino acid deletion studies have revealed that the

C-terminal truncations of a-MSH also possess the anti-

inflammatory properties of a-MSH with the minimum-

effective sequence confined to the last 3 residues, Lys-D-

Pro-Val [19, 20]. IL-1b (193–195) is a structural analogue

of this tripeptide, which serves as a non-selective antago-

nist of IL-1R1 [21]. Therefore, under pro-inflammatory

conditions, IL-1b (193–195) can antagonize the actions of

IL-1b and thus exerts anti-inflammatory and anti-nocicep-

tive activities [10]. Our results demonstrate for the first

time that IL-1b (193–195) can inhibit the IL-1b (187–207)-

induced hyperthermia. In addition to PGE2 stimulation,

other pathways may also mediate the hyperthermic effect

of IL-1b (187–207), such as the activation of nuclear factor

kappa-light-chain-enhancer of activated B cells (NF-kB)

[22], expression of adhesion molecules and chemokine

receptors [23] and/or production of pro-inflammatory

cytokines [10]. The a-MSH-related tripeptide IL-1b (193–

195) may interfere with these pathways and consequently

inhibit the hyperthermic effect of IL-1b (187–207) [9]. In

contrast, under non-inflammatory conditions, IL-1b (193–

195) does not influence the body temperature [24]. Our

results are in concordance with these observations.

Various diseases of the CNS, including meningo-

encephalitis [25], neurodegenerative disorders [26], vas-

cular lesions [27], or status epilepticus [28] are accompa-

nied by elevated levels of IL-1b. a-MSH and a-MSH-

related peptides, such as IL-1b (193–195) can inhibit the

actions of IL-1b and therefore can exert anti-inflammatory

and neuroprotective effects [9, 26]. The physiochemical

properties and expected low costs of production render IL-

1b (193–195) suitable for the future treatment of neuro-

degenerative disorders and additionally, immune-mediated

inflammatory skin and bowel diseases, fibrosis, allergic and

inflammatory lung disease, ocular inflammation, and

arthritis [10]. IL-lb domain in position 187–207 may also

serve as a novel target for treatment of these disorders.

Acknowledgments This work was supported by grants from ETT

(01/2006), ETT355-08/2009, TAMOP-4.2.1, TAMOP 4.2.2-A-11/1/

KONV-2012-0052 and the Neuroscience Research Group of the

Hungarian Academy of Sciences.

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0 30 60 90 120 150 180

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