UNIVERSIDADE ESTADUAL PAULISTA
“JÚLIO DE MESQUITA FILHO”
Instituto de Ciência e Tecnologia
Campus de São José dos Campos
DOI: https://doi.org/10.4322/bds.2023.e3666
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Braz Dent Sci 2023 Jan/Mar;26 (1): e3666
LITERATURE REVIEW
Insights on the role of cytokines in carious lesions
Insights
sobre o papel das citocinas em lesões cariosas
Lucélia Lemes GONÇALVES1 , Eui KIM2, Janaína Freitas BORTOLATTO2 , Marilia Rabello BUZALAF3 ,
Lulwah ALRESHAID4 , Anuradha PRAKKI2
1 - Universidade Estadual de Sao Paulo, Instituto de Ciencias e Tecnologia de Sao Jose dos Campos, Departamento de Dentistica
Restauradora, Sao Jose dos Campos, SP, Brasil.
2 - University of Toronto, Faculty of Dentistry, Restorative Department, Toronto, Ontario, Canada.
3 - Universidade de Sao Paulo, Faculdade de Odontologia de Bauru, Departamento de Ciencias Biologicas, Bauru, SP, Brasil.
4 - King Saud bin Abdulaziz University for Health Sciences, College of Dentistry, Department of Restorative Dental Sciences, Riyadh,
Saudi Arabia.
How to cite: Gonçalves LL, Kim E, Bortolatto JF, Buzalaf MR, Alreshaid L, Prakki A. Insights on the role of cytokines in carious lesions.
Braz. Dent. Sci. 2023;26(1):e366. https://doi.org/10.4322/bds.2023.e3666
ABSTRACT
Objectives: The dentin-pulp immune response to caries pathogenesis is still poorly understood due to the complex
interplay of the involving processes. The aim of this review was to explore the role of cytokines and its relevance in
the pathogenesis of dental caries. Results: Dental caries can result in a host inammatory response in the dental
pulp, characterized by the accumulation of inammatory cells leading to the release of inammatory cytokines
such as Interleukin-4 (IL-4), Interleukin (IL-6), Interleukin-8 (IL-8) and Tumor necrosis factor–α (TNF-α). IL-4
seems to be correlated to the depth of carious lesions; IL-6 is strongly correlated to caries disease and is considered
a potent biomarker; IL-8 can be a potent biomarker for both caries and other changes present in the pulp and,
its release is correlated to TNF-α and IL-6; TNF-α plays an important role not only in caries progression, but also
in other pathological processes. Conclusion: Specic mediators have a great potential to serve as biomarkers
alluding to the presence and progress of caries disease, urging further investigations in the eld.
KEYWORDS
Biomarkers; Cytokines; Dental caries; Dental pulp; Interleukins.
RESUMO
Objetivo: A resposta imune da dentina-polpa à patogênese da cárie ainda é pouco compreendida devido à
complexa interação dos processos envolvidos. O objetivo desta revisão foi explorar o papel das citocinas e
sua relevância na patogênese da cárie dental. Resultados: A cárie dentária pode resultar em uma resposta
inamatória do hospedeiro na polpa dental, caracterizada pelo acúmulo de células inamatórias levando à
liberação de citocinas inamatórias como, Interleucina-4 (IL-4), Interleucina (IL-6), Interleucina-8 (IL-8) e
fator de necrose tumoral–α (TNF-α). IL-4 parece estar correlacionada com a profundidade das lesões cariosas;
IL-6 está fortemente correlacionada com a doença cárie e é considerada um potente biomarcador; IL-8 pode ser
um potente biomarcador tanto para cárie quanto para outras alterações presentes na polpa e sua liberação está
correlacionada com TNF-α e IL-6; TNF-α desempenha um papel importante não apenas na progressão da cárie,
mas também em outros processos patológicos. Conclusao: Mediadores especícos têm um grande potencial
para servir como biomarcadores quanto à presença e progressão da doença cárie, o que incita a necessidade de
mais investigações nesse campo.
PALAVRAS-CHAVE
Biomarcadores; Citocinas; Cárie dentária; Polpa dentária; Interleucinas.
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Gonçalves LL et al.
Insights on the role of cytokines in carious lesions
INTRODUCTION
Dental caries is one of the most common
chronic human diseases worldwide which is
multifactorial, biolm-mediated, diet modulated,
non-communicable and dynamic disease.
It is determined by a variety of factors such
as biological, behavioral, psychosocial, and
environmental. As consequence of this process, a
carious lesion develops as a result of net mineral
loss of dental hard tissues [1-3]. During caries
process the pulp immune response is triggered
to respond in inammation [4].
Pulpal tissues are equipped with defense
cells and inammatory mediators that mediate
and maintain the host response to microbial
infection. Odontoblast cells direct response
to caries is the release of cytokines and
antimicrobial peptides, while indirectly causing
the migration of immunocompetent cells such
as cytokines [4].
Cytokines are products of activated
monocyte–macrophage cells that may play an
important role controlling the inflammatory
response to bacterial infection contributing
to the initiation and progression of dental
caries [5]. The literature accepts the arrangement
of cytokines into major structural families such as
chemokines, interferons, tumour necrosis factors,
and interleukins [6].
Dental caries process is responsible to
trigger a host inflammatory response in the
dental pulp, characterized by the accumulation
of inflammatory cells leading to the release
of inflammatory cytokines such as IL-4,
IL-6, IL-8 and TNF-α [6]. Some studies have
pointed out that these mediators could be
potential targets for therapeutic strategies in
the treatment of inflammatory diseases [7].
However, the diagnostic process of caries disease
till these days relies on clinical, visual, and
radiographic methods, and its inflammatory
component remains unexplored, which is a
recognized source for diagnosis at the molecular
level [6]. Therefore, the role of cytokines
in the pathogenesis of dental caries entails
further investigation. Accordingly, regarding
the importance of the immune system and its
components in inammation of the dental tissue,
this review was designed to explore the role of
cytokines and its relevance in the pathogenesis
of dental caries.
DENTAL CARIES
Nowadays, dental caries is dened as a result
of dysbiotic changes in the oral biolm community
with predominant acid-tolerant and acid-producing
microbiota and low levels of benecial bacteria
mainly mediated by frequent intake of fermentable
sugars and carbohydrates [3,8].
The dynamic caries process consists of rapidly
alternating periods of tooth demineralization
which is caused mainly by the action of lactic
acid and, remineralization through the buffering
action of saliva but, the presence of uoride can
also prevent demineralization. Caries lesions
occurs when the demineralization takes place
over enough time bypassing remineralization
process at teeth surface [9-11].
The enamel barrier disruption makes dentin
more susceptible to degradation by Gram-
positive bacteria such
as streptococci
,
lactobacilli
,
and
actinomyces
, which further becomes the
leading cause of pulpal inflammation [12].
The metabolic activity and proliferation of these
microorganisms release bacterial components
into dentinal tubules and lead to diffusion
toward the peripheral pulp. The recognition
of bacterial components by host cells such as
odontoblasts at the dentin-pulp interface triggers
host protective events including antibacterial,
immune, and inammatory responses including
the production of pro-inammatory mediators
such as chemokines and cytokines [13,14].
However, the host immune response also plays
a pivotal role in tissue destruction [12].
When dentin is demineralized, collagenases
are uncovered and activated, playing an important
role in caries progression [7]. The progression of
caries also induces degradation of the collagen
matrix. Host-derived proteolytic enzymes such as
matrix metalloproteinases (MMPs) and cysteine
cathepsins are activated by low pH. Cysteine-B and
-K, and many types of matrix metalloproteinases
such as MMP-2, -8, -3 and -9 have been identied
in dentin carious lesions [7,15,16]. In addition,
host proteases are not only found in dentin but
also in saliva [7]. MMPs-8 and -9 are the most
predominant salivary MMPs and efficiently
degrade exposed dentinal collagen [7,15]. During
dentin demineralization as the disease progress,
high levels of cytokines and growth factors, such
as TNF-α and TGF-β are released [17]. Previous
studies have reported increased expression of
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different cytokines in caries-affected dental pulp
and/or odontoblasts [18].
Despite several studies exploring mediators
of the immune response, little is still understood
about the impact of cytokines on caries disease
because of its complexity. Clearly understanding
the role of cytokines and their correlation with
caries disease is important to establish useful
tools for diagnosis and treatment.
CYTOKINES - IMMUNE AND
INFLAMMATORY RESPONSE
Cytokines
Cytokines are classied as soluble proteins
with low molecular weight (≈6–70 kDa),
secreted by a variety of cells (macrophages,
lymphocytes, natural killer (NK) cells, stromal
cells, and mast cells) which have a specific
effect on communications and interactions
between cells. Cytokine is a general name; other
names are based on its origin or functions such
as lymphokine (generated by lymphocytes),
monokine (generated by monocytes), chemokine
(cytokines with chemotactic activities), interferons
(IFNs), tumor necrosis factors (TNFs), colony-
stimulating factors (CSFs), and transforming
growth factors (TGFs), and interleukin (cytokines
generated by one leukocyte and acting on other
leukocytes) [19,20]. Cytokine production can
play an important role on health conditions as
they are responsible for de dynamic regulation
of the maturation, growth, and responsiveness of
immune cells [20].
Cytokines can generate and maintain host
responses to microbial infection. These molecules
are secreted by the host living cells as paracrine
or autocrine signals to recruit cells of the immune
system (chemokines), proinammatory cytokines,
or anti-inflammatory cytokines [18]. Pro-
inammatory cytokines facilitate inammatory
reactions and contribute to the stimulation of
immunocompetent cells, they are interleukin
1 beta (IL-1β), interleukin 6 (IL6), interleukin
8 (IL-8), interleukin 12 (IL-12), tumor necrotic
factor-α (TNF-α), and interferons among others.
On the opposite side, anti-inammatory cytokines
such as IL-1 receptor antagonist (IL-1RA),
interleukin 4 (IL-4), IL-6, interleukin 10 (IL-10),
interleukin 11 (IL-11), interleukin 13 (IL-13), and
transforming growth factor (TGF-β), suppress
immune cells and inhibit inammation [21]. This
classication helps to understand the pathways
triggered by the host response in consideration of,
a single cytokine may be secreted by different cells
and act as shows both anti-inammatory or pro-
inammatory activities depending on the context,
generating multiple immune responses [20].
Cytokines can be classied based on their
cellular source as type 1 cytokine response
which is produced by a cluster of differentiation
4 (CD4)+ T-helper 1 (Th1) cells and characterized
by cell-mediated response, with interferon-γ (IFN-
γ), as the typical cytokine in association with
interleukin 2 (IL-2), Tumor Necrosis Factor-β
(TNF-β) and interleukin 12 (IL-12) and, type
2 which is produced by CD4+ Th2 cells and
marked by the production of one or more B-cell
activities, with IL-4 being the classical cytokine
and an association with interleukin 5 (IL-5), IL-6,
IL-10, and IL-13 [20,22,23].
Cytokines are redundant in their activity,
because analogous functions can be stimulated by
different cytokines. They are often produced in a
cascade, as one cytokine stimulates its target cells
to make additional cytokines. Cytokines can also
act synergistically, additively, or antagonistically
as a network (Figure 1) inhibiting or enhancing
the action of other cytokines in complex ways [19].
Cytokines, dentin and pulp tissue
An association between the dentin or the
pulp and the presence of cytokines is not a newly
Figure 1 - Cytokine network. When pathogens interact with cells
close to the pulpal core, inflammatory events occur leading to
increase in the number of different cytokines. During these events,
cytokines can play a role synergistically or antagonistically with one
another, which lead to enhancement or inhibition of actions of other
cytokines. This relationship among the different cytokines (IL-1, IL-4,
IL-10, IL-12, IFN-γ, and TNF-α shown in the image) is complex.
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observed concept. In 1991, McFarlane and Meikle
were among the rst to see a relation between
cytokine levels and oral diseased conditions [24].
Dentin has been recognized as a bioactive
matrix which stores numerous collagenous and
non-collagenous proteins. Growth factors and
cytokines in dentin have been also identied in
several studies. These studies reveal dentin as
a source of signaling molecules and highlight
dentin’s bioactive ability to regenerate tissues
following injury [25]. During an inammatory
response complex, biological and biochemical
processes are involved with cells of the immune
system. Biological mediators such as cytokines
also play an extremely important role in mediating
the process of inflammation [26]. In 2004, a
study conducted by Silva et al. [27] evidenced
that the release of dentin-derived bioactive
factors resulting from exposure or destruction
of dentin matrix could contribute to chemotaxis
and aggregation of inflammatory cells, and
determine the maintenance or resolution of the
inammatory process. They demonstrated that
dentin factors orchestrate at least one part of
the scenario, favoring building or destruction
of the tissue. Some of these biologic mediators
show potential for clinical use in areas such as
periodontology and restorative dentistry. This
led to speculation that the physiological and
natural biochemical properties of dentin could be
exploit for the development of novel treatment
modalities and diagnostic technologies [12].
Pulpal fibroblasts synthesize and secrete
the pulpal collagen matrix and, also produce
inflammatory mediators in response to caries-
related bacteria. Dendritic cells exist underneath
the odontoblast layer and are known to increase
during carious challenge to identify foreign bodies
for immune cells [28,29]. When bacterial infection
is present, the invading pathogens and their
products or components, and the dentin matrix
constituents secreted during demineralization are
rst encountered by odontoblast cells located at the
periphery of the pulp. As bacterial infection invades
the underlying dental tissue and deeper, pulpal
inammation exacerbates, becoming more intense
and prevalent. This is characterized by elevated
pro-inammatory gene expression and concurrent
elevation of immune cell inltrates. In addition, the
dentin matrix contains a complex variety of pro-
and anti-inammatory molecules. Furthermore,
increase in the number of immune system cells
that infiltrate the pulp (such as lymphocytes,
neutrophils, macrophages, and plasma cells) is
shown with further progression of the lesion [30].
Odontoblasts protect the underlying dental
tissue against the bacterial invasion, functioning
as a barrier [31]. The cells are immunocompetent
and have the ability to orchestrate an inammatory
response [32]. As the bacterial infection progresses
into deeper underlying dental tissue, changes
in the bacterial biolm composition are seen,
and destructive effects on the host cells such as
pulpal cell deaths may occur [33]. Thus, further
progression of molecular interactions between
the cells and pathogens close to the pulpal core
results in an aggravation of inammatory events.
In such events, the increase of some cytokines
(both pro- and anti-inammatory) such as IL-1β,
IL-2, IL-4, IL6, IL-8, IL-10, IFN-γ, tumor necrotic
factor-α (TNF-α), TGF-β1, vascular endothelial
cell growth factor (VEGF), C-C chemokine ligand
2 (CCL2), human beta-defensins (hBDs) and
CXC chemokine ligand 10 (CXCL10), has been
reported to happen [4,18,34].
Expressed in a wide range of host and immune
structural cells are the toll-like receptors (TLRs),
a class of proteins consisting of cell membrane-
bound and endosome-bound receptors [35]. TLRs
have regulatory functions in the innate immune
system, by recognizing pathogen-associated
molecular patterns (PAMPs). Bacterial surface
components are TLR ligands; some of them are
lipotechoic acids, agellin, lipopolysaccharides,
lipoproteins and peptidoglycans. Other ligands
detected by toll-like receptors are nucleic acid
ligands originating from pathogens. Following the
invasion of the underlying tissues, TLRs-1, -2, -3,
-4, -5, -6, and -9 are expressed on pulpal broblasts
and odontoblasts and further bind to the bacterial
components. The binding stimulates activation of
the nuclear factor kappa B (NF-κB) intracellular
signaling pathway, which is responsible for
molecular inammatory response regulation [34].
In fact, a number of cellular signaling pathways
are active during inflammation. In response
to nuclear factor kappa B signaling pathway,
cytokines and chemokines are released as potent
signaling proteins. Cytokines and chemokines
regulate inflammatory and immune responses
and functions via detection and binding of
specic membrane-bound receptors. Furthermore,
through second messenger signaling systems,
these molecules act to modulate biochemical
responses and gene expression in target cells [36].
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In fact, cytokines are the modulators of the
immune and inammatory response and other
factors [12]. Therefore, cytokine measurements
are important as these proteins can be widely
used as biomarkers [4]. The analysis of cytokines
levels in various biological uids such as serum,
blood, stool, saliva, and sweat, provides valuable
information regarding the diagnosis, stage, and
prognosis of various diseases, which makes possible
to understand and predict disease progression and
monitor the effects of treatment [20,37], including
oral diseases such as caries [38].
Cytokines and dental caries
The inflammatory and immunological
response of the dentin-pulp to caries is complex
and initiates acute and chronic activation of the
innate immune responses leading to pulpitis. This
process involves several factors that can lead to
increase levels of cytokines. Some studies have
shown that cytokines can contribute to initiation
and progression od dental caries. However, their
role in the pathogenesis of dental caries still not
totally understood [5,14].
The progress of carious infection into pulp-
dentin can affect the microora composition,
lowering the proportion of Gram-positive aerobic
bacteria and increasing levels of Gram-negative
anaerobic bacteria [39]. Consequently, the
environment at deep carious lesion becomes
more anaerobic and complex with a high
bacterial diversity. The odontoblasts barrier
can recognize caries-related pathogens, such as
Streptococcus mutans
, which has an important
impact on the initial lesion and pulpal pathology,
prevails on shallow lesions and, play important
roles in the innate immune system of dental pulp
tissues [14,40]. Host cells, including odontoblasts
and other immune cells, will increase their
expression in response to infection. Moreover,
components of dentin released by carious
bacterial acids during the demineralization
process can contribute to the increasing levels of
inammatory mediators [13,41].
Several previous studies have shown increased
expression of various cytokines in caries-affected
dental pulp and/or odontoblasts including IL-1β,
IL2, IL-4, IL-6, IL-8, IL-10, IL11, IFN-γ and TNF-
α, TGF-β1, and others [13,18,32,34,40,41].
The induction of these cytokines was also shown
in odontoblast-like cells and cultured pulp-derived
broblasts exposed to bacteria or their products
in
vitro
[23,40] such as
Lactobacilli
and
Streptococci
microorganisms particularly associated with the
development of caries lesions [42].
Some authors have even correlated levels of
expression of certain cytokines with the severity
of the caries disease [43].
Relevant interleukins in carious process
Several studies have been carried out to
explore cytokines as possible biomarkers for
caries disease. A biomarker act as an indicator of a
normal biological process, a pathological process,
or a response to a pharmacological treatment and,
provide information about the susceptibility or
risk to develop a disease [44].
Cytokines acts modulating the immune
and inflammatory response among other
factors therefore, can help to diagnose and
monitor several oral cavity diseases, including
caries [12,38]. Among these studies, some
cytokines draw attention with great potential as a
tool to aid in the diagnosis of caries such as IL-4,
IL-6, IL-8 and TNF-α and, seems to be correlated
to each other (Table I).
The evidence of increasing levels of IL-4 in deep
carious lesions associated with a close association
between IL-4 and IL-6 expression shed light on the
importance to better investigate the role of IL-4 in
caries [54,55]. The TNF- α and IL-6 are considered
key mediators of acute inammation. Higher levels
of the TNF- α and IL-6 can lead to a lower number
of broblasts and osteoblasts that contributes in the
demineralization process of teeth and development
of caries disease [6,45] IL-8 and TNF-a play an
important role in immunity of the oral cavity [50]
TNF-α is an effector cytokine and its production
leads to oral diseases besides. Moreover, it is a
stronger inducer of interleukin-8 [45]. According
to ElSalhy et al. [46], the ratios of IL-6/IL-10 and
IL-8/IL-10, and levels of IL-8 have the potential to
indicate pulpal inammation in caries exposure
cases.
Interleukin-4
Interleukin-4 is an important cytokine that is
responsible for the secretion of other cytokines.
It functions as a potent regulator of immunity
secreted primarily by mast cells, Th2 cells,
eosinophils and basophils [56,57].
Among several interleukins, IL-4 has a
signicant inuence on shaping immune responses.
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Table I - Cytokine expression during caries progression
Study Objective Method Key findings
Hahnetal. (2000) [40]
Evaluated the hypothesis that cytokines induced
by antigens from
Streptococcus mutans
could play
a major role in inducing the initial T-cell response
in the pulp
Examined
S. mutans
ability to elicit cytokines by
stimulating T cells and analyzed the presence of
cytokines in dental pulp at mRNA level
Inflammatory cytokine mRNAs (IL-4, IL-10, IFN-γ)
were identified in dental pulp. All three cytokines
of different frequencies- IFN-γ (67%), IL-10 (29%),
and IL-4 (19%) - were observed in shallow caries.
However, there was no differences in the frequencies
of cytokines in deep caries. The presence of
S.
mutans
correlated with the IFN-γ levels in the pulp.
McLachlanetal.
(2004) [41]
Examined the expression levels of potential
molecular mediators for pulpal inflammation, and
correlated the levels with oral disease severity
Semi quantitative reverse transcriptase PCR
analysis was used to examine the pulpal tissue
samples of S100 family members, multiple
cytokines and ENA-78
In carious teeth, significantly positive correlation
between the expression of IL-1β and S100A8,
between IL-6 and epithelial neutrophil-activating
peptide 78 ENA-78), between S100A8 and
collagen-1α, and among IL-1β, IL-6, IL-8, TNF- α
and ENA-78. Thus, a complex molecular immune
response involving many cytokines occurs during
caries infection.
Horstetal. (2011) [18]
Examined gene expression profiles of cytokines
that are generated in response to caries disease
and aimed to build a mechanistic response model
and downstream signaling network
Described gene expression profiling of cytokines
and related immune components induced in
odontoblast layer and pulp of normal teeth.
cDNA array analysis was conducted to study the
expression levels of cytokines, chemokines and
receptors in response to caries in human teeth.
Interleukins, chemokines and receptors were
differentially upregulated in odontoblast layer
during carious infection. Also, pro-inflammatory
cytokines Interleukin-1 alpha (IL-1α), IL-1 β, and
TNF-α- were highly expressed in odontoblast layer
of carious teeth.
Gornowiczetal.
(2012) [45]
Investigated to test the hypothesis that changes
in the levels of IL-6, IL-8, and TNF-α in saliva are
seen in patients with dental caries
Presence of IL-6, IL-8, and TNF-α were examined
in caries and healthy patients through Enzyme
Linked Immunosorbent Assay (ELISA)
The results showed a positive correlation between
IL-8 and TNF-α. Also, the study indicates that
significant increased levels of TNF-α, IL-6 and IL-8
in saliva and dental caries disease.
ElSalhyetal. (2013) [46]
Measured and compared the levels of cytokine
molecules TNF- α, IFN-γ, IL-2, IL-6, IL-8, and IL-10
found in pulpal blood from normal pulps, pulps
with asymptomatic caries exposure, and pulps
with irreversible pulpitis
Blood samples from pulp exposure sites in teeth
with normal pulps, those with asymptomatic
caries-exposed pulps, and those with irreversible
pulpitis were obtained. High-sensitivity ELISA was
used to determine their cytokine levels.
High levels of TNF- α, IFN-γ, IL-6, IL-8, and IL-10
were found in teeth with caries-exposed pulps
and those with irreversible pulpitis. Teeth with
irreversible pulpitis showed higher concentrations
of IL-2 and IL-10, and lower levels of IL-8 were
found in those with caries-exposed pulps. The
IL-6/IL-10 ratio and IL-8/IL-10 were higher in
irreversible pulpitis cases. Levels of IL-8 levels
and IL-6/IL-10 and IL-8/IL-10 ratios may have
the potential to act as indicators for pulpal
inflammation in caries-exposed teeth.
Menonetal. (2016) [47]
Evaluated the level of salivary IL-6 in children with
early childhood caries (ECC) and to compare its
levels before and after full mouth rehabilitation.
Saliva samples were collected from children with
ECC prior and 3-month post dental treatment.
The salivary IL-6 levels were analyzed using the
ELISA method.
High levels of salivary IL6 were found. Full mouth
rehabilitation significantly contributed to reducing
salivary IL6 levels.
Ribeiroetal. (2018) [21]
Evaluated salivary concentrations of the
proinflammatory cytokines- VEGF, TNF-α, and
IL-6-, and associated them with sugar intakes,
obesity, and the presence of dental caries in
mothers and in their children.
Case-control study involving caries-free children
and children with early childhood caries (ECC),
and their mothers. Salivary levels of VEGF, IL-6
and TNF-α were analyzed.
Children with caries had a 63% higher median
salivary VEGF and twofold higher mean IL-6
levels compared to caries-free children. Mothers
of children with ECC showed higher mean of
salivary IL-6 levels compared to those of children
without ECC.
Sharmaetal. (2017) [6]
Evaluated levels of inflammatory cytokines in
saliva of children with early childhood caries
(ECC), in order to assess their potential use as
non-invasive biological markers.
ELISA was used to determine salivary
concentrations of TNF- α, IL-6, and IL-8 in healthy
children and children with ECC, before and after
rehabilitative intervention.
The severity of caries disease and the
cytokine concentrations were correlated.
Significant increase in the TNF- α, IL-6, and IL-8
concentrations may act as indicators as non-
invasive, diagnostic and prognostic markers in
early childhood caries.
Nazemisalmanetal.
(2019) [48]
Evaluated the level of TNF-α in saliva and its
association with caries in different age groups of
adolescents and children.
In this case-control study, 128 children and
adolescents were divided to four age groups. In
each group, half of the individuals had no decay
(control group) and the other half had more than
4 decayed teeth (case group). Salivary level of
TNF-α was measured using ELISA.
Decay plays an important role in increasing of
TNF-α in non-stimulatory saliva. However, there is
no confirming evidence of the direct effect of age
on immune function yet.
Giudiceetal.
(2020) [49]
Evaluated salivary immunoglobulin A (s-IgA) and
IL-6 in saliva of children and its correlation to
tooth decay severity.
Fifty-nine patients were divided into two groups:
caries free and caries active. Saliva levels of IgA
and IL-6 were analyzed by ELISA.
Salivary IL-6 levels were significantly higher in
children with active caries when compared with
the caries-free group, while the s-IgA rate showed
no significant differences between the two groups.
Husseinetal.
(2020) [50]
Evaluated the level of pro-inflammatory cytokines
such as IL-6, IL-8, and TNF-α in the saliva of
smokers with dental caries and non-smokers
(control group).
Whole saliva from 32 smokers aged 35-46 years
with dental caries and 16 healthy subjects were
analyzed, to measure IL-6, IL-8, and TNF-α levels
by ELISA.
The results indicated links between production of
TNF-α, IL-6, and IL-8 in smokers saliva and dental
caries disease.
Tasoetal. (2020) [51]
Estimated the effect of caries disease and
treatment on concentrations of IL-2, IFN-γ,
IL-12, Interleukin-17A (IL-17A), IL-13, IL-10, IL-6,
IL-5, IL-4, interleukin 22 (IL-22), TNF-α, and
IL1-β in gingival crevicular fluid (GCF) of caries
affected teeth before (B), 7 (7D) and 30 (30D)
days post-treatment and to compare them with
concentrations from healthy teeth.
GCF samples were collected baseline as well as
7D and 30D. The biomarker measurement was
performed using multiplex flowcytometry.
Significantly higher levels of IFN-γ, IL-1β, IL-2, IL-4
and IL-6 were found in caries affected teeth when
compared to healthy teeth. The levels of cytokines
post-treatment showed general trend of increase
when compared to baseline, that was significant
for IL-22 and interleukin 17 (IL-17) at 7D, while IFN-γ
was significantly increased at 7D compared to the
healthy teeth. At 30D, IFN-γ, TNF-α, IL-17 and IL-4
levels were significantly increased when compared
to healthy teeth, while IL-2 levels were significantly
higher than baseline levels.
Govulaetal. (2021) [12] To assess and compare the salivary levels of IL-6
in patients before and after caries removal.
A pre-treatment saliva sample was collected. The
post-treatment saliva samples were collected. The
IL-6 levels were analyzed through ELISA.
After the complete removal of caries and
restorative procedures the levels of IL-6 reduced
significantly.
Paquéetal. (2021) [52]
Evaluated the potential of protein and salivary
bacterial markers for evaluating the disease status
in healthy individuals or patients with gingivitis
or caries.
Saliva samples from healthy individuals, patients
with gingivitis and, patients with deep caries
lesions were collected and analyzed for 44
candidate biomarkers.
Computational analysis revealed four biomarkers
(IL-4, IL-13, Interleukin-2 receptor alpha chain
(IL-2-RA), and eotaxin/CCL11) to be of high
importance for the correct depiction of caries.
These findings suggest IL-4, IL-13, IL-2-RA, and
eotaxin/CCL11 as potential salivary biomarkers for
identifying non-invasive caries.
Ramírez-De los
Santosetal. (2021) [53]
Evaluated the concentrations of IL-6, IL-8, IL-15,
and interleukin 18 (IL-18) in the salivary samples of
children with caries and obesity.
Salivary samples of children with normal weight
and with obesity were used to measure the
cytokine levels via the ELISA technique.
The results of this study suggested that IL-6 has
a significant effect on both obesity and caries.
However, IL-8 is more related to caries, and IL-15
is more related to obesity.
7
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Gonçalves LL et al.
Insights on the role of cytokines in carious lesions
Gonçalves LL et al.
Insights on the role of cytokines in carious lesions
IL-4 is a protein that has pleiotropic effects on
multiple cell types. IL-4 receptor is composed
of an α subunit that is associated with IL-4’s
binding afnity and a γ subunit which also act as
a component of other cytokine receptors. When
IL-4 binds to its receptor, T cell proliferation
and differentiation into helper T cells are
induced [55]. Once activated, peripheral CD4+ T
cells produce and secrete various cytokines. These
cytokines act as autocrine growth/differentiation
factors, and consequently, T cells proliferate in
number and differentiate into effector cells [55].
Effector helper T (Th) cells can be categorized
into subsets according to the pattern of the
cytokine secretion. Type 1 Th cells secrete IL-2,
IFN-γ, and TNF-α; and Type 2 Th cells produce
interleukin 3 (IL-3), IL-4, IL-5, and IL-6 [56].
For instance, Type 1 Th cell functions are essential
for cell-mediated immunity; and Type 2 Th cells
aid in B cell function and immunoglobulin class
switching. The vital immune responses dominated
by IL-4 may be reective of the inuences of Type
2 Th cells during microbial infections [58]. As host
immune responses are activated, and different
cytokines are secreted, Type 2 Th cells produce,
among other cytokines, IL-4 and IL-6 [56]. The type
2 immune response promotes B-cell activities, with
IL-4 acting as the prototypic cytokine molecule
and in association with IL-6 [59]. Therefore,
action on Th 2 lymphocytes to secrete cytokines
during pulpal inammation leads to production
and increased levels of IL-4 and IL-6, releasing
the two pro-inammatory cytokines within the
diseased tissue [60].
IL-4 is considered an inammatory mediator
with a signicant increase in the reversible and
irreversible stages of dental pulp inammation
compared to normal pulp tissue [61]. Although
there are several investigations on IL-6 levels and
its link to dental caries, there is limited data in
the literature in general on the levels of different
interleukins in pulp in association with carious
lesions, especially IL-4.
Hahn et al. [40] observed the existence of IL-4,
along with IFN-γ and IL-10, in the pulpal carious
lesions. Also, it showed that
S. mutans
, which is
associated to shallow lesions, promoted minimal
induction of IL-4. These ndings suggested that
there may be a correlation between the level of
IL-4 and the depth of carious lesions; in other
words, the concentration of IL-4 may act as a
differentiator among shallow and deep carious
lesions. Paqué et al. [52] investigated the potential
protein markers for evaluating the disease status
in healthy individuals or patients with gingivitis or
caries. They observed that the presence of IL-4 in
deep caries lesions was remarkable in comparison
to healthy teeth, suggesting that this cytokine can be
considered an excellent marker to make distinction
among caries, healthy, and gingivitis. Moreover,
Taso et al. [51] verified the increased level of
IL4 even in the presence of shallow caries lesions.
Although there are several investigations
on IL-6 levels and its link to dental caries, there
is limited data in the literature in general on
the levels of different interleukins in pulp in
association with carious lesions, especially IL-4.
Therefore, investigations on the expression
and/or pathways that lead to the expression of
IL-4 in association with carious lesions may render
interesting ndings on the role of the cytokines
in caries process. Not only its association with
IL-6 may be indicative of the important role of
IL-4, but also its differing levels of expression
with regards to the depth of the carious lesions.
Interleukin-6
The human interleukin 6 is a helical-shaped
protein composed of 212 amino acids, is a
pleiotropic cytokine produced by a variety of
nonimmune and immune cells which is responsible
to regulate many aspects of the local immune
response, such as T-cells and macrophage cells.
IL-6 have pro- and anti-inflammatory effects,
involved in inammation response, tissue injury
and regenerative processes [12,62]. This cytokine
is strongly upregulated in bacteria-challenged
inflamed pulps
in vivo
and in odontoblasts
in vitro
upon TLR2 engagement [63,64]. IL-6 has
an important role in the differentiation and
regulation of T helper (Th)2, Th17, and T
regulatory (Treg) phenotypes, and it stimulates
the secretion of acute-phase proteins including
lipopolysaccharide-binding protein. This cytokine
plays an important role accelerating pulpal
inammation and it may also participate in the
edema formation by an increase in vascular
permeability induced by the intradentinal
penetration of Gram-positive bacteria [12,13].
The presence of IL-6 has been correlated
to different oral diseases such as oral lichen
planus, periodontitis and dental caries [50,62].
Gornowicz et al. [45] showed that the levels of
IL-6 were increased in patients with dental caries.
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Insights on the role of cytokines in carious lesions
Gonçalves LL et al.
Insights on the role of cytokines in carious lesions
Menon et al. [47] observed that caries activity
and poor oral hygiene may increase the level of
IL-6 in saliva. Giudice et al. [49] in a clinical study
observed high levels of salivary IL-6 in children
with active caries in comparison to the caries-free
group. In another study conducted by the same
research group [62] the authors suggested that
low-quality plaque control, plaque accumulation
and gingival inammation can induce an increase
of IL-6 levels in gingival crevicular uid in children.
Govula et al. [12] showed that there is a strong
correlation between IL-6 levels and the extent and
severity of carious lesions and, that the levels of
IL-6 reduced signicantly after the complete removal
of caries and restorative procedure. Taso et al. [51]
in controlled split-mouth study observed that caries
affected teeth exhibited signicantly higher levels
of IL-6 when compared to healthy teeth.
The role of Interleukin-6 in caries disease
has been extensively studied and the results are
promising. The literature has pointed this cytokine
as potent biomarker for caries disease since it has
shown a strong correlation with pulpal inammation
and immunosenescence with dental caries [10].
Interleukin-8
Interleukin- 8 (IL-8) is considered the
prototype molecule in the chemokine class
and is classied as an inammatory stimulant
cytokine [50]. IL-8 is synthesized by a vast
number of different cells, such as monocytes,
macrophages, neutrophils, broblasts, T-cells,
endothelial cells, and chondrocytes [6,50].
The main function of IL-8 is to attract and
activate neutrophils cells [4,6]. IL -8 seems to
be involved in processes such as inammation,
immune response control, hematopoiesis, and
oncogenesis. This cytokine is synthesized in
acute inflammatory response contributing to
host defence and persists for a relatively long
time at the site of inflammation [65]. IL-8 is
normally released, following the cells’ stimulation
by lipopolysaccharide molecules, early pro-
inflammatory cytokines such as TNF-α and
interleukin 1 (IL-1) or bacteria. Therefore, can be
rapidly synthesized at local sites of inammation,
as one of the most potent cytokines and the
main neutrophil chemo-attractant. Moreover, it
is speculated that elevated levels of IL-8 lead to
stimulation of TNF-α [4,45].
Elevated levels of IL-8 were associated to
gingivitis and periodontitis. A systematic review
performed by Hirsch et al. [4] correlated the
presence of IL-8 to irreversible pulpitis in comparison
to normal pulp samples. In regard to caries disease,
Ramírez-De los Santos et al. [53] observed the
correlation between the presence of IL-8 and caries.
Hussein et al. [50] investigated salivary levels of
pro-inammatory cytokines (IL-6, IL-8, and TNF-α)
in the saliva of smokers with dental caries and the
control (non-smokers) and, they observed a high
level of IL-8 in the presence of dental caries. In a
study conducted for Gornowicz et al. [45] the saliva
cytokines levels in patients with dental caries were
investigated, the author observed a high level of
IL-6, IL-8, and TNF-α in dental caries in comparison
to healthy patients. Sharma et al. [6] investigated
salivary levels of inammatory cytokines in children
with early childhood caries in early and severe
stages and, before and after restorative procedures
and from the healthy controls in order to assess their
potential as non-invasive biomarkers. The salivary
levels of IL-6, IL-8 & TNF-α were significantly
higher in patients before the intervention and
got significantly reduced after the restorative
procedure. This result indicated that these cytokines
are signicantly associated with severity of dental
caries. Moreover, the authors found correlation
among IL-6, IL-8 & TNF-α with each other in both
pre-operative and post-operative groups.
Studies indicate that IL-8 can be a potent
biomarker for both caries and other changes
present in the pulp. It is worth mentioning that
many studies correlate the presence of these three
cytokines that seem to act in similar situations.
Tumor necrosis factor–α
Tumor necrosis factor–α is a pleiotropic
cytokine that stimulates inammation by leading
to recruitment of leukocytes, inducing vasodilation,
and stimulating the production of pro-inammatory
cytokines [66]. This cytokine is considered a cell
signaling protein involved in systemic inammation
that composes the acute phase reaction and chronic
inflammation and immune response. Besides,
TNF-α stimulates phagocytes for cellular apoptosis,
bone resorption, and the synthesis of IL-1, IL-6, and
chemokines [6,67].
TNF-α is a pro-inammatory cytokine originally
discovered as a protein with necrotizing effects in
mouse-transmissible tumors. This cytokine has an
important role in host defense and inammatory
responses with multiple biologic effects. TNF-α
acts on the growth, differentiation, and function
9
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Gonçalves LL et al.
Insights on the role of cytokines in carious lesions
Gonçalves LL et al.
Insights on the role of cytokines in carious lesions
of all cell types and seems to be an integral part of
inammatory and immunological events [45,48].
TNF-α is present in all vital human pulpal
tissues it is considered an important cytokine
for evaluating the inflammatory process [67].
A previous study [68] showed that irreversible
symptomatic pulpitis presented a high concentration
of TNF-α which were slightly less in irreversible
asymptomatic pulpitis, although healthy samples
got the lowest TNF-α concentration.
It is well known that bacterial antigens of caries
disease can induce the release of proinammatory
cytokines such as IL-1 and TNF-α which are rapidly
produced by activated monocytes/macrophages
to recruit neutrophils and monocytes to the site
of infection [69]. Gornowicz et al. [45] found an
elevation of salivary cytokines such as TNF-α in
dental caries patients and, that there is correlation
among this cytokine, IL-6, IL-8 in saliva and dental
caries disease. Sharma et al. [6] evaluated salivary
levels of inammatory cytokines in children with
early childhood caries and found an elevated level
of TNF-α and, that the presence of this cytokine is
correlated with the severe stage of the caries disease.
The study conducted by Nazemisalman et al. [48]
concluded that tooth decay plays an important role
in increasing cytokine TNF-α in non-stimulatory
saliva. In contrary, Hussein et al. [50] observed
that the level of TNF-α in the saliva of smokers with
dental caries were not signicant in comparison
to control. However, for Hirsch et al. [4] TNF-α
may be a notable objective marker for laboratory
determination of the extent of inflammation,
which could be useful for caries diagnosis.
TNF-α plays an important role not only in
caries progression, but also in other pathological
processes [70, 71]. Therefore, further studies
should be conducted in order to better understand
the correlation of this cytokine with the other
mediators present in the carious process.
CONCLUSION
The dentin-pulp immune response to caries
pathogenesis is still poorly understood due to
the complex interplay of the involving processes.
This literature review showed that the presence
of IL-4 seems to be strongly correlated with the
progress of the carious lesion. Whereas, IL-6,
IL-8, and TNF-α are markers of the presence
of caries disease. Moreover, the expression of
these interleukins are correlated with each other.
The latest ndings on the role of cytokines on
caries process shows that some specic mediators
have a great potential to serve as biomarkers
alluding to the presence and progress of caries
disease, urging further investigations in the eld.
Author’s Contributions
LLG: Conceptualization. LLG: Methodology.
LLG, EK, JFB: Writing – Original Draft Preparation.
AP: Writing – Review & Editing. MRB, LA, AP:
Visualization. MRB, LA, AP: Supervision.
Conict of Interest
No conicts of interest declared concerning
the publication of this article.
Funding
The authors declare that no nancial support
was received.
Regulatory Statement
A regulatory statement is not applicable as
this is a review article.
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12
Braz Dent Sci 2023 Jan/Mar;26 (1): e3666
Gonçalves LL et al.
Insights on the role of cytokines in carious lesions
Gonçalves LL et al.
Insights on the role of cytokines in carious lesions
Anuradha Prakki
(Corresponding address)
University of Toronto, Faculty of Dentistry, Restorative Department, Toronto,
Ontario, Canada.
Email: a.prakki@dentistry.utoronto.ca Date submitted: 2022 Oct 18
Accept submission: 2022 Nov 16
