24

Dental Journal
(Majalah Kedokteran Gigi)

2020 March; 53(1): 24–29

Research Report

Effect of various inductions of sleep deprivation stress on 
proinflammatory cytokine levels in gingival crevicular fluids of 
white male Wistar strain rats (Rattus novergicus) 

1 2 3Pratiwi Nur Widyaningsih, Fitranto Arjadi and Erlina Sih Mahanani
1Postgraduate student of Biomedical Study Program, Faculty of Medicine, Universitas Jenderal Soedirman, Purwokerto - Indonesia
2Department of Anatomy, Faculty of Medicine, Universitas Jenderal Soedirman, Purwokerto - Indonesia
3Department of Dental Biomedic, Faculty of Medicine and Health Science, Universitas Muhammadiyah Yogyakarta, Yogyakarta - Indonesia

ABSTRACT
Background: Stress that is induced by sleep deprivation can modulate the damage of periodontal tissue by elevating the levels of 
proinflammatory cytokines (i.e. IL-1β and TNF-α). The effects of sleep deprivation can be resolved with sleep recovery. Gingival crevicular 
fluid (GCF) is fluid in sulcular gingiva which acts as an oral biomarker for evaluating periodontal abnormalities. Purpose: The aim of 
this study was to determine the effect of various induction methods of sleep deprivation stress on cytokine levels in GCF of white male 
Wistar strain rats (Rattus novergicus). Methods: The study method was true experimental with a posttest-only control group design. 
Thirty male Wistar rats were randomly divided into five groups: paradoxical sleep deprivation (PSD), total sleep deprivation (TSD), 
partial sleep deprivation with sleep recovery for five days (PSD+SR), total sleep deprivation with sleep recovery for five days (TSD+SR) 
and a healthy control group. Data were analysed via one-way ANOVA to determine differences between groups. Result: The results 
showed the highest level of IL-1β and TNF-α was found in the PSD group. One-way ANOVA analysis showed significant differences 
(p<0,05) of IL-1β level between PSD and control groups, PSD and PSD+SR groups and PSD and TSD+SR groups; in contrast, the 
analysis of TNF-α levels showed significant differences (p<0,05) between PSD group to control group, PSD to PSD+SR group and TSD 
to TSD+SR group. Conclusions: There is an effect of various induction methods of sleep deprivation stress on proinflammatory 
cytokines (IL-1β and TNF-α).

Keywords: paradoxical sleep deprivation; proinflamatory cytokines; sleep deprivation; total sleep deprivation; sleep recovery

Correspondence: Pratiwi Nur Widyaningsih, Postgraduate student of Biomedical Study Program, Faculty of Medicine, Universitas 
Jenderal Soedirman. Jl. Dr Soeparno Purwokerto, Banyumas, Indonesia 53122. E-mail: pratiwinurwidyaningsih@gmail.com

INTRODUCTION

Stress is a common problem in modern life, causing a 
significant decrease in the number of sleep hours among 
adults and children. Epidemiological data show that sleep 
disorders and short duration of sleep have negative impacts 
on human physical health.1

Sleep deprivation causes an increase in lymphocyte 
activation, so that it produces more proinflammatory 
cytokines (IL-1, IL-6, IL-17 and TNF-α), thereby increasing 
the risk of inflammation or damage to tissue, including 
periodontal tissue. In addition, due to an imbalance between 
the formation and elimination of reactive oxygen species 
(ROS), sleep deprivation is also related to the mechanism of 

oxidative stress. However, the impact of sleep deprivation 
can be corrected by sleep recovery, which results in a 
decrease in lipid peroxidase and free radical productionm, 
thus restoring antioxidant activity in inhibiting oxidative 
stress.2–5

Proinflammatory cytokines play an important role 
in inflammation and bone resorption; therefore, they are 
important parameters in periodontal research. The presence 
of IL-1β in gingival crevicular fluid (GCF) can stimulate 
the occurrence of alveolar bone resorption. TNF-α produced 
by macrophages and lymphocytes has the same effect as 
IL-1β. Tumor necrosis factor-α (TNF-α) can stimulate cell 
proliferation and differentiation such as osteoblasts and 
osteclasts. The ability of TNF-α to stimulate the production 

Dental Journal (Majalah Kedokteran Gigi) p-ISSN: 1978-3728; e-ISSN: 2442-9740. Accredited No. 32a/E/KPT/2017. 
Open access under CC-BY-SA license. Available at http://e-journal.unair.ac.id/index.php/MKG
DOI: 10.20473/j.djmkg.v53.i1.p24–29

mailto:pratiwinurwidyaningsih@gmail.com
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25Widyaningsih, et al./Dent. J. (Majalah Kedokteran Gigi) 2020 March; 53(1): 24–29

of enzymes that damage the matrix and bone recession 
activities plays an important role in damage caused by 
periodontal disease.6,7

Gingival crevicular fluid is a product of cells (transudates) 
found in the gingival sulcus originating from post-capillary 
venules from the gingival plexus, and it can be influenced 
by an inflammatory response in the area around the gingival 
sulcus. Cytokines detected in GCF can be used as oral 
biomarkers in evaluating periodontal disease conditions or 
in periodontal treatment results.7 Research on the effect of 
various induction methods of sleep deprivation stress on 
proinflammatory cytokine levels, IL-1β and TNF-α levels 
in GCF of white male Wistar strain rats (Rattus norvegicus) 
has never been done before; therefore, the authors are 
interested in exploring this topic.

MATERIALS AND METHODS

-This study used a true experimental approach with a post
test-only control group design for white male Wistar strain 
rats (Rattus norvegicus) aged 3–4 months with a weight of 
200–300 grams. The rates were given various inductions 
of sleep deprivation stress with paradoxical model sleep 
deprivation (PSD) with 20 hours given stress and four 
hours rest for five days; total sleep deprivation (TSD) with 
24 hours given stress and no rest for five days; paradoxical 
sleep deprivation was continued with sleep recovery for 
five days (PSD + SR); and total sleep deprivation was 
continued with sleep recovery for five days (TSD + SR). 
All stress models used a single platform method (SPM) tank 
measuring 23 x 23 x 35 cm where one rat in a flowerpot 
was equipped with muscle atonia which gave a shock effect 
automatically every 10 minutes in experimental animals.8 

The subjects of this study were 30 white male Wistar 
strain rats (Rattus norvegicus) aged 3–4 months with a 
weight of 200–300 grams obtained from the Pharmacology 
and Therapy Department, Faculty of Medicine, Universitas 
Gadjah Mada. All experiments conducted in this study have 
been approved by the Ethics Commission of the Faculty of 
Medicine, Universitas Jenderal Soedirman No. Ref. 4704/
KEPK/X/2018. The experimental animals were randomly 
divided into five groups: PSD (KI) group, TSD group 
(KII), PSD + SR group (KIII), TSD + SR group (KIV), 
and healthy control group (KV); each group consisted of 
six white rats.

All experimental animal samples were acclimatised for 
seven days before the induction of various sleep deprivation 
methods. After acclimatisation, groups I and III were given 
PSD stress treatment for 120 hours, and groups II and IV 
were given TSD stress treatment for 120 hours, while 
group V was not treated with stress. Groups I, II and III 
then returned to their original state while groups IV and 
V continued with sleep recovery for 120 hours and then 
returned to their original conditions.

After the induction of stress deprivation was completed, 
GCF was taken using filter paper with a size of 2.55 

mm x 14.19 mm with a thickness of 0.16 mm with the 
intracrevicular absorption method. Previously, filtered 
paper was carried out by gas ethyleneoxide (EOG) 
sterilization to prevent bacterial or fungal contamination 
that could affect variables. The GCF retrieval method was 
carried out by controlling saliva with cotton in the area 
around the anterior gingival of the mandibula, inserting 
filter paper into the gingival sulcus at a depth of 1 mm in 
the anterior gingival of the mandibula of the white male 
Wistar strain rats for 30 seconds. GCF retrieval was carried 
out after the treatment was completed, and the extraction 
time was adjusted to the circadian rhythm of the rats at 
07.00–10.00.

Filter paper containing GCF was immediately inserted 
into an eppendorf tube containing 200µl of Phosphate 
Buffered Saline (PBS) (Gibco®, USA) with a pH of 7.4; 
it was then homogenised using a vortex mixer. GCF was 
stored at -20oC or allowed to melt at 2–8oC, and then 
centrifuged from 2,000 to 3000 rpm for 20 seconds. 
Measurement of IL-1β and TNF-α levels was carried out 
using the enzyme-linked immunosorbent assay (ELISA) 
sandwich method which was read on an ELISA reader with 
an absorbance wave of 450 nm. Data were tabulated and 
tested for normality by the Saphiro-Wilk and Levene test 
for its homogeneous. Data were then analysed by one-way 
ANOVA to determine differences between groups. 

RESULTS

The results of the study on the measurement of IL-1β levels 
revealed mean levels of IL-1β of experimental animals in 
each group described in Figure 1. Figure 1 shows that the 
highest mean of IL-1β level experimental animals is in the 
PSD group with a mean of 453.05 ± 48.81 pg/L. The lowest 
mean of IL-1β levels was found in the PSD + SR group: 
380.40 ± 24.65 pg/L.

The results of the Shapiro-Wilk and Levene statistical 
analysis showed that the data of each group were normally 
distributed and homogeneous. The statistical test continued 
using the parametric one-way ANOVA test, and the result 
of the significance obtained is p<0.05. These results indicate 
the effect of sleep deprivation treatment on IL-1β levels. 
A post-hoc LSD test was carried out to determine if there 
are significant differences between each treatment in the 
sample groups.

Table 1 shows groups with significant results (p<0.05), a 
significant control group for the PSD group and vice versa. 
The PSD group was significant for the PSD + SR group 
and vice versa. The TSD + SR group is significant for the 
PSD group and vice versa. In contrast, the TSD group did 
not show significant results (p>0.05) for all groups.

The results of the study on the measurement of TNF-α 
levels obtained mean levels of TNF-α in each group as 
described in Figure 2. Figure 2 shows that the highest mean 
of TNF-α level in experimental animals was in the PSD 
group, with a mean of 377.89 ± 69.00 ng/ml. The lowest 

Dental Journal (Majalah Kedokteran Gigi) p-ISSN: 1978-3728; e-ISSN: 2442-9740. Accredited No. 32a/E/KPT/2017. 
Open access under CC-BY-SA license. Available at http://e-journal.unair.ac.id/index.php/MKG
DOI: 10.20473/j.djmkg.v53.i1.p24–29

http://e-journal.unair.ac.id/index.php/MKG
http://dx.doi.org/10.20473/j.djmkg.v53.i1.p24-29


26 Widyaningsih, et al./Dent. J. (Majalah Kedokteran Gigi) 2020 March; 53(1): 24–29

 

0,00
50,00

100,00
150,00
200,00
250,00
300,00
350,00
400,00
450,00
500,00

PSD TSD PSD+SR TSD+SR Control

M
ea

n 
of

IL
-1
β

(p
g/

L)
Le

ve
ls

453.05 ±48.81

380.40±24.65
407.96±18.44

380.40±24.65 

418.21±30.58 

Figure 1. Mean of IL-1β levels in experimental animals.

 

0,00

50,00

100,00

150,00

200,00

250,00

300,00

350,00

400,00

PSD TSD PSD+SR TSD+SR Control

M
ea

n 
of

T
N

F-
α

(n
g/

m
l)

Le
ve

ls

273.68 ±41.27

337.89 ±69.00 
311.53 ±65.86 

217.31 ±26.40 

305.06 ±59.31 

Figure 2. Mean bar chart of TNF-α levels in experimental animals.

Table 1. Post-Hoc LSD test, mean IL-1β levels in sleep deprivation stress treatment in each group

Groups
p-value

Control PSD TSD PSD+SR TSD+SR
Control 0.046* 0.651 0.231 0.354
PSD 0.134 0.004* 0.007*
TSD 0.120 0.192
PSD+SR 0.788
TSD+SR

Notes: * p<0.05

Table 2. Post-Hoc LSD test, mean of TNF-α levels in sleep deprivation stress treatment in each group

Groups
p-value

Control PSD TSD PSD+SR TSD+SR

Control 0.317 0.842 0.016* 0.339
PSD 0.420 0.002* 0.057
TSD 0.010* 0.251
PSD+SR 0.108
TSD+SR

Notes: *p<0.05

Dental Journal (Majalah Kedokteran Gigi) p-ISSN: 1978-3728; e-ISSN: 2442-9740. Accredited No. 32a/E/KPT/2017. 
Open access under CC-BY-SA license. Available at http://e-journal.unair.ac.id/index.php/MKG
DOI: 10.20473/j.djmkg.v53.i1.p24–29

http://e-journal.unair.ac.id/index.php/MKG
http://dx.doi.org/10.20473/j.djmkg.v53.i1.p24-29


27Widyaningsih, et al./Dent. J. (Majalah Kedokteran Gigi) 2020 March; 53(1): 24–29

mean of TNF-α levels was found in the PSD + SR group: 
217.31 ± 26.40 ng/ml.

The results of the Shapiro-Wilk and Levene statistical 
analysis showed that the data were normally distributed 
and homogeneous. The statistical test continued using 
the parametric one-way ANOVA test, and the results of 
significance obtained was p<0.05. These results indicate 
that there is an effect of sleep deprivation treatment on 
TNF-α levels. Post-hoc LSD tests were carried out to 
determine if there are significant differences between each 
treatment in the sample group.

Table 2 shows groups with significant results (p<0.05), 
which is the significant control group for the PSD group 
and vice versa. The PSD group was significant for the PSD 
+ SR group and vice versa. The TSD group was significant 
for the PSD + SR group and vice versa. In contrast, the 
TSD + SR group did not show significant results (p> 0.05) 
for all groups.

DISCUSSION

Based on the results of the study, the mean of IL-1β level 
was highest in the PSD group, while the lowest mean 
of IL-1β level was found in the PSD + SR group. This 
indicates that sleep deprivation stress has an impact on 
IL-1β levels, and the administration of sleep recovery after 
sleep deprivation treatment can reduce IL-1β levels. When 
sleep deprivation occurs, endogenous and endotoxin factors 
will induce the production of proinflammatory cytokines, 
including IL-1, TNF-α, and nuclear factor kappa B (NF-
κB). Furthermore, proinflammatory cytokines along with 
neurochemicals play an important role in the regulation of 
sleep in the non-rapid eye movement sleep (NREM) phase, 
resulting in an increase in proinflammatory cytokines in 
the NREM phase and will decrease during the rapid eye 
movement sleep (REM) phase. This is in line with the 
results in this study, wherein the mean of IL-1β level of the 
PSD group was significant (p <0.05) for the control group 
who were not given stress exposure; hence, in the control 
group, there was no increase in IL-1β levels.9–11 

Sleep deprivation can be divided into acute sleep 
deprivation and chronic sleep deprivation. Acute sleep 
deprivation is a long period of an awake condition, whereas 
chronic sleep deprivation is an accumulation of sleep 
deprivation that occurs over several days. According to 
Landolt et al. (2014),9 partial sleep deprivation (PSD) 
is included in acute deprivation (short-term), whereas 
total sleep deprivation (TSD) is included in chronic sleep 
deprivation (long-term). Stress exposure can have an effect 
on the immune response, where acute stress deprivation 
sleep can induce innate immunity, antigen presentation, 
antibodies and cytokine production.12,13

IL-1β levels in the PSD and TSD groups in this study did 
not show a significant difference (p> 0.05), although IL-1β 
levels in the PSD group were higher than the IL-1β levels 
in the TSD group. This shows that sleep deprivation stress 

in the PSD group can produce more IL-1β than the TSD 
group. This condition is caused by the immune response 
in the acute phase of sleep deprivation activating Toll-like 
receptors (TLR), which will trigger gene transcription 
in NF-κB and increase production of IL-1β and other 
proinflammatory cytokines, so that IL-1β levels in the 
PSD group are higher than in TSD groups. In addition, 
interleukin 1 (IL-1α and IL-1β) is a key mediator in the 
acute phase response to infected hosts.9,14

Some studies have suggested that sleep can play an 
anti-stress role through the mechanism of inhibiting the 
HPA axis. Sleep recovery can improve the impact of 
sleep deprivation by returning the HPA axis interaction 
to normal. Sleep deprivation conditions can activate the 
HPA axis, playing an important role in the occurrence of 
stress, inducing an increase in the production of IL-1β, and 
returning to normal after sleep recovery.15–17

IL-1β levels in this study had significant results (p<0.05) 
in the PSD group against the PSD + SR group. The IL-
1β levels in the PSD + SR group decreased significantly 
when compared with the PSD group. This shows that the 
administration of sleep recovery in the PSD + SR group 
succeeded in reducing levels of IL-1β. Sleep recovery can 
improve the effects of sleep deprivation by returning the 
HPA axis interaction to normal, reducing the hormone 
cortisol so that it results in a decrease of CRH. Sleep 
deprivation will stimulate the activation of the HPA axis 
and induce the CRH hormone, which is the main regulator 
in the wake condition, inhibiting the non-REM (NREM) 
and REM sleep phase.14,18,19

This study also showed significant results (p<0.05) in 
TSD + SR groups for the PSD group, as the mean of IL-1β 
levels in TSD + SR group was lower than the PSD group. 
This suggests that the administration of sleep recovery 
exposure in the TSD + SR group also reduced IL-1β 
levels. The PSD group was included in the acute stress 
category so that levels of IL-1β produced were higher when 
compared with the TSD + SR group, which was included 
in the category of chronic stress to be then given additional 
treatment, namely sleep recovery.

The administration of sleep recovery to PSD and TSD 
treatment in the PSD + SR and TSD + SR groups in this 
study had almost the same results, which showed a non-
significant difference (p>0.05), although the IL-1β levels 
in the PSD + group SR show lower results than the TSD 
+ SR group. It demonstrated that administering sleep 
recovery may successfully reduce levels of IL-1β after 
treatment of PSD and TSD. Sleep recovery can restore 
body performance, especially in the REM cycle recovery, 
where REM sleep deprivation for more than 72 hours can 
cause increased levels of IL-1β, IL-6, IL-17A, and TNF-α 
in rats.16,17

Changes in TNF-α levels due to stress deprivation 
sleep have been widely demonstrated in previous studies. 
Based on the results of this study, sleep deprivation stress 
has an impact on the levels of TNF-α, where the highest 
levels of TNF-α were highest in the PSD group, and the 

Dental Journal (Majalah Kedokteran Gigi) p-ISSN: 1978-3728; e-ISSN: 2442-9740. Accredited No. 32a/E/KPT/2017. 
Open access under CC-BY-SA license. Available at http://e-journal.unair.ac.id/index.php/MKG
DOI: 10.20473/j.djmkg.v53.i1.p24–29

http://e-journal.unair.ac.id/index.php/MKG
http://dx.doi.org/10.20473/j.djmkg.v53.i1.p24-29


28 Widyaningsih, et al./Dent. J. (Majalah Kedokteran Gigi) 2020 March; 53(1): 24–29

lowest levels of TNF-α were found in the PSD + SR 
group. Sleep deprivation stress plays a role in modulating 
cytokine production, one of which is TNF-α. The body’s 
response to stress can change the homeostasis system 
because stress will induce activation of the HPA axis and 
sympathetic nervous system. The activation of the HPA 
axis will cause glucocorticoid production in the adrenal 
cortex. Stress exposure that occurs continuously has an 
effect on adrenaline response quickly, so glucocorticoids 
experience a rapid increase in exposure to acute stress, 
whereas, in chronic stress, the body can control these 
conditions so that glucocorticoid production decreases 
and can be lost. In chronic sleep deprivation, there is an 
increase in cortisol levels which causes desensitisation 
of glucocorticoid receptors, resulting in a decrease in 
glucocoticoid levels.5,14,20 

This study showed a higher increase in TNF-α levels in 
the PSD group than in the TSD group. However, the results 
of the post-hoc LSD analysis did not show a significant 
difference (p>0.05) between the two groups. This shows 
an increase in TNF-α levels in the PSD group which can 
be seen when compared with the TSD group. As in the IL-
1β pattern, stress exposure PSD treatment is included in 
the category of acute stress induction, where the immune 
response in the acute phase of sleep deprivation will 
activate receptors such as toll-like receptors (TLR) that 
will transcript genes at NF-κB and increase production of 
TNF-α and other proinflammatory cytokines.9,21

Similar to IL-1β, TNF-α plays a role in the sleep 
regulatory mechanism in the hypothalamus and locus 
coeruleus (LC) in the NREM phase. The administration 
of sleep recovery treatment in experimental animals can 
reduce the activity of the HPA axis so that it can reduce 
TNF-α levels. This study had significant results (p <0.05), 
namely in the PSD group for the PSD + SR group, where 
TNF-α levels in the PSD + SR group decreased after being 
given a sleep recovery treatment. This shows that exposure 
to sleep deprivation stress with the treatment of PSD + 
SR has been successful in reducing TNF-α levels. Sleep 
recovery can improve the effects of sleep deprivation by 
returning the interaction from the HPA axis to normal. 
A decrease in activation of the HPA axis can reduce the 
production of TNF-α.16,22,23 

The administration of sleep recovery in the PSD + SR 
group in this study was also significant (p<0.05) for the 
TSD group. The PSD + SR group had lower TNF-α results 
when compared with the TSD group. This happens because 
the administration of sleep recovery in the SR PSD + group 
can reduce levels of TNF-α. Sleep can reduce substances 
that can stimulate TNF-α production and can inhibit the 
corticotropin-releasing hormone (CRH). Reduction in 
CRH secretion will reduce activation of the HPA axis so 
that TNF-α levels decrease.15

The PSD + SR and TSD + SR groups showed almost 
the same results so that there was no significant difference 
(p>0.05). TNF-α levels in the TSD + SR group were higher 
when compared to the PSD + SR group. This happens 

because the PSD + SR group still has time to sleep every 
day and also gets additional time for sleep recovery so 
that the levels of TNF-α in the PSD + SR group are lower 
than the TSD + SR group. Subjects who were given TSD 
for 24 hours and 48 hours full, and then given a sleep 
recovery treatment for 24 hours, will recover from the sleep 
deprivation by 72% for TSD for 24 hours and have 42% 
for TSD for 48 hours.24

In conclusion, the induction of various stress deprivation 
stress methods has an impact on the levels of proinflammatory 
cytokines namely IL-1β and TNF-α in GCF white male 
Wistar strain rats (Rattus norvegicus). The administration 
of sleep recovery after the induction of sleep deprivation 
stress has an effect on levels of IL-1β and TNF-α in GCF 
white male Wistar strain rats (Rattus norvegicus).

ACKNOWLEDGEMENTS

We would like to thank to Research and Community 
Service Institute of Jenderal Soedirman University for the 
research funding from Improvement Fund Research Grant 
Batch III in 2018, Research Laboratory, Pharmacology 
Laboratory, and Experimental Animal Laboratory of 
Faculty of Medicine, Jenderal Soedirman University for 
the facilites provided.

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Dental Journal (Majalah Kedokteran Gigi) p-ISSN: 1978-3728; e-ISSN: 2442-9740. Accredited No. 32a/E/KPT/2017. 
Open access under CC-BY-SA license. Available at http://e-journal.unair.ac.id/index.php/MKG
DOI: 10.20473/j.djmkg.v53.i1.p24–29

http://e-journal.unair.ac.id/index.php/MKG
http://dx.doi.org/10.20473/j.djmkg.v53.i1.p24-29