J Oral Pathol Med (2015) 44: 114
doi: 10.1111/jop.12142
REVIEW ARTICLE
Inflammation-related cytokines in oral lichen planus: an
overview
Rui Lu1,2, Jing Zhang1, Wei Sun1, Gefei Du1,2, Gang Zhou1,2
1
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine
Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, PR China; 2Department of Oral Medicine, School
and Hospital of Stomatology, Wuhan University, Wuhan, China
Cytokines are powerful mediators which play a central
role in both innate and adapted immune responses.
Aberrant productions of cytokines may lead to the onset
of immune deficiency, allergy or autoimmunity, which
are involved in the mechanisms of various immune-
mediated inflammatory diseases. Oral lichen planus
(OLP) is a chronic inflammation disease affecting the
oral mucosa with unknown aetiology. Previous studies
have described the abnormal expression patterns of
various inflammation-related cytokines, such as IL-1, 2,
4, 5, 6, 8, 10, 12, 17, 18, TGF-b, IFN-c and TNF-a, in
lesions, saliva, serum and peripheral blood mononuclear
cells from patients with OLP, which may reflect the
immune dysregulation status and emerge as central
players in the immunopathogenesis of OLP. Besides,
the gene polymorphisms of several cytokines such as IFN-
c, TNF-a, IL-4, IL-10 have been found to be involved in the
susceptibility of OLP. In this review, we gave a brief
introduction of the characteristics and biological func-
tions of these inflammation-related cytokines and sum-
marized for the first time the current knowledge on the
involvement of inflammation-related cytokines in OLP.
Further research on the exact roles of these cytokines
will aid the understanding of the pathogenesis and the
identification of novel therapeutic approaches of OLP.
J Oral Pathol Med (2015) 44: 114
Keywords: cytokine; oral lichen planus; overview
Introduction
Oral lichen planus (OLP) is a chronic inammatory disease
affecting the oral mucosa, sometimes in combination with
Correspondence: Prof. Zhou Gang, DDS, PhD, Department of Oral
Medicine, School and Hospital of Stomatology, Wuhan University, Luoyu
Road 237, Wuhan, China. Tel: +86 27 87686213, Fax: +86 27 87873260,
E-mail: gordonzhou@tom.com
Accepted for publication November 14, 2013
2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
wileyonlinelibrary.com/journal/jop
extraoral lesions on skin, genitalia and nails (1). Clinically,
OLP may manifest as different forms, including reticular,
erythematous and erosive lesions (2). The oral lesions of
OLP are persistent, rarely undergo self-remission, and have
a potential for malignant transformation (1). Histologically,
OLP is characterized by a dense subepithelial inltration of
lymphocytes, increased numbers of intraepithelial lympho-
cytes and the degeneration of basal keratinocytes (3).
Although the etiopathology of OLP is still unknown, a
large number of evidences have supported a central role for
immune dysregulation in the pathogenesis of OLP, in which
both the antigen-specic and non-specic mechanisms are
involved (24). The immune dysregulation in OLP is
reected, to a large extent, by the aberrant productions of a
great range of inammatory mediators both in the local
lesions and peripheral blood, which may play important
regulatory roles in the interactions between keratinocytes, T
cells and many other cell types (511). Among these
inammatory mediators, cytokines are the most major types.
Cytokines are small peptide proteins that can be
synthesized and secreted by various immune cells and
non-immune cells (12). They function as key signalling
molecules in the communication between cells by binding to
specic receptors on target cells and initiating intracellular
signalling cascades, result in the changes of phenotype and
function of target cells via altered gene regulation (13, 14).
Most cytokines are pleiotropic molecules and may exert
distinct effects depending on the target cell types and the
environment (15). They also can induce each others
productions in autocrine, paracrine and endocrine fashions,
to form complex regulatory networks (12, 13). In immune
system, cytokines are powerful regulators and play a central
role in controlling the direction, extent and duration of both
the innate and adapted immune responses (15). Aberrant
productions of cytokines may lead to the onset of immune
deciency, allergy, autoimmunity, inammation, which are
involved in the pathogenesis of various immune-mediated
inammatory diseases (15, 16).
In OLP, a large number of studies have described the
abnormal expression patterns of various inammation-
related cytokines in lesions, saliva, serum and peripheral
 Cytokines in oral lichen planus
Lu et al.

2
blood mononuclear cells (PBMCs) from patients, including
interleukins (ILs), transforming growth factor-b (TGF-b),
interferon-c (IFN-c) and tumour necrosis factor-a (TNF-a;
Summarized in Table. 1) (5, 6, 810, 1723). In addition,
gene polymorphisms of several cytokines in patients with
OLP were reported, which may represent genetic factors in
the susceptibility of disease (2427). Hitherto, there is no
comprehensive summary on the cytokines in OLP. In this
review, we gave a brief introduction of the characteristics
and biological functions of each cytokine and then summa-
rize for the rst time the current knowledge on the
involvement of these cytokines in the pathogenesis of OLP.
Interleukins
The term interleukin (IL) was rst described a number of
secreted molecules produced by leucocytes, but later, it has
been found that they are also produced by a wide variety of
cell types (28). Nowadays, ILs are known as a group of
cytokines with multiple functions in nearly all aspects
of inammation and immunity, including immune cell
proliferation, differentiation, maturation and activation (28).
So far, IL-1, 2, 4, 5, 6, 8, 10, 12, 17 and 18 were found to be
the major ILs involved in the pathogenesis of OLP.
IL-1
Characteristics
The term of IL-1 is a general name for two distinct proteins,
IL-1a and IL-1b, which are encoded by two separate genes but
signal through the same receptor complex and have identical
biological activities (29). IL-1 is synthesized by a wide variety
of cells. Whereas IL-1b is mainly produced by monocytes and
macrophages, IL-1a expression is more widespread and
highly expressed by keratinocytes and endothelial cells (29).
Biological functions
Both IL-1a and IL-1b have potency and extensive func-
tions. The main biological activity of IL-1 is the stimulation
of T-helper cells, which are induced to secrete IL-2 and to
express IL-2 receptors. Further studies have identied that
IL-1 is an important mediator of inammatory response and
immune responses (30, 31). IL-1a and IL-1b can rapidly
activate multiple different cell types including T cells,
neutrophils, monocytes, eosinophils and macrophages, and
stimulate the production of other cytokines such as TNF-a,
IL-6, IL-8, as well as itself. In addition, IL-1 also promotes
proliferation of bone marrow cells, B lymphocytes, neu-
trophils, macrophages and platelets (31, 32).
IL-1 in OLP
Firstly, IL-1+ cells, which had the surface characteristics as
a monocyte/macrophage subset, were found to be abundant
in the mucosal lesions of OLP (33). This nding was
validated by a recent work by Ge et al. (17), which also
revealed positive staining of IL-1b in the spinous and basal
keratinocytes and inltrated lymphocyte in OLP lesions. In
ex vivo studies, Yamamoto et al. found that the numbers of
cells producing IL-1b and the IL-1b concentrations in the
culture supernatants of both keratinocytes and tissue-inl-
trating mononuclear cells (TIMC) isolated from the OLP
lesional tissues increased compared with their counterparts
from inamed and normal gingival (6, 34). Additionally,
stimulated by IL-1b, keratinocytes and TIMC from OLP
lesions produced more TNF-a, IL-6 and granulocyte
macrophage colony-stimulating factor (GM-CSF) than the
keratinocytes from healthy gingival (6, 34). These ndings
revealed the present and activity of IL-1b in the local
environment of OLP, suggesting its regulatory role in the
cytokine network in OLP.
In recent years, Rhodus et al. found signicantly elevated
levels of IL-1a in whole unstimulated saliva (WUS),
mixture of saliva and isotonic saline oral rinse (Saliva-
NaCl), and lesion tissue transudates (TT) from patients with
OLP compared with healthy controls (5, 35). Moreover, the
increased level of IL-1a in WUS from patients with OLP
could decrease to a normal level after the dexamethasone

Table 1 Summary of expression patterns and gene polymorphisms of cytokines in oral lichen planus

Cytokine Lesion Cell source Saliva Serum PBMC Gene polymorphism

IL-1 Unclear Keratinocyte, TIMC Increased Unclear Unclear Not found
IL-2 No difference TIMC Unclear Inconsistent No difference Not found
IL-4 Inconsistent TIMC Inconsistent Inconsistent Unclear Higher frequencies of 590 C/C
and 1098 G/G genotypes
IL-5 Increased Unclear Unclear No difference Inconsistent Unclear
IL-6 Increased T cells, keratinocyte, Increased Increased Inconsistent Higher frequency of 174 G/G genotype
TIMC
IL-8 Not detected Not detected Increased Increased Unclear Lower frequency of 251 AA genotype
and 251 A/+781 C haplotype, higher
frequency of 251 T/+781 C haplotype
IL-10 Increased TIMC Unclear Inconsistent Decreased Higher frequencies of 1082A/ 819T/ 592A
haplotype
IL-12 Increased Epithelial cell Unclear Unclear Inconsistent Not found
IL-17 Increased CD4+T cell Unclear Inconsistent Unclear Unclear
IL-18 No difference Unclear Increased Increased Unclear Higher frequencies of 607 C/C genotype
TGF-b Decreased Subepithelial inltrate Unclear Inconsistent Inconsistent Not found
IFN-c Increased Subepithelial inltrate, Inconsistent Inconsistent Decreased Higher frequencies of UTR 5644 T/T genotype
CD4+Th1 cells and and +874 T/T genotype
CD8+T cell
TNF-a Increased Keratinocytes, mast cells Increased Inconsistent Decreased Inconsistent
and CD4+T cells

J Oral Pathol Med


treatment (36). In addition, in OLP cases with moderate
dysplasia, the levels of IL-1a were signicantly increased
without difference from OSCC (37). These results indicated
diagnostic and prognostic value of IL-1a for monitoring
disease activity, therapeutic response as well as the malig-
nant transformation in patients with OLP.
Hepatitis C virus (HCV) infection is thought to contribute
to the development of OLP, but the mechanism is still
unclear. Femiano and Scully reported that the viral genome
of HCV was not detected in the oral epithelium from
patients with OLP, but there was a reduction in IL-1 in the
oral epithelium from patients with OLP who were positive
for HCV (38). The results suggested that HCV infection
status may inuence the levels of cytokines, including IL-1,
in the OLP lesions, thus exerting an indirect effect in the
development of OLP (38).
It is demonstrated that cytokines genes polymorphisms are
associated with the susceptibility to develop some immune-
mediate conditions. The gene polymorphisms of IL-1 cluster
were investigated in patients with OLP, however, no
relationship between the gene polymorphisms of IL-1 cluster,
and the susceptibility of OLP was found (25, 39).
IL-2
Characteristics
IL-2 was actually the rst interleukin molecule to be
discovered, which is a instrumental leukocytotrophic hor-
mone in the bodys response to microbial infection and in
discriminating between foreign and self-antigens (40).
Under physiological conditions, IL-2 is produced mainly
by CD4+T cells, but also by CD8+T cells, B cells and NK
cells followed by cell activation (41). Several secondary
signals are required for maximal expression of IL-2. In vitro,
the synthesis of IL-2 can be inhibited by dexamethasone or
cyclosporin A (41). IL-2 mediates its effects by binding to
IL-2 receptors (IL-2R), which are expressed by lymphocytes
that are responsible for cellular immunity (40).
Biological functions
IL-2 is a strong growth factor for T cells, which can induce the
expansion of both CD4+ and CD8+ T cells (41). IL-2 has
complex roles in modulating differentiation of CD4+ T cells
(42). It can prime and maintain the differentiation of Th1 and
Th2 but inhibit Th17 differentiation (42, 43). Moreover, IL-2
is critical for the maintenance of regulatory T (Treg) cells
(43). For CD8+T cells, IL-2 can induce the differentiation and
expansion of effector cell, augments cytolytic activity, as well
as promotes generation and proliferation of memory CD8+ T
cells (42). In addition, IL-2 promotes the proliferation of
activated B cells and enhances antibody secretion. IL-2 also
stimulates the proliferation of NK cells, monocytes and
macrophages (41, 42).
IL-2 in OLP
The expressions of IL-2 and its receptor IL-2R were
consistently found in the OLP lesions (9, 18, 32, 4447).
Meanwhile, the expression of IL-2R, which was considered
as a marker of T-cell activation, was located on the
inltrated T lymphocytes, especially the cytotoxic/suppres-
sor subsets (32, 4447). In vitro, TIMC from OLP lesions
Cytokines in oral lichen planus
Lu et al.
3
can generate more IL-2 compared with TIMC from the
gingiva (6). Considering its biological function, recombi-
nant IL-2 (rIL-2) was used to expand the T-cell lines
isolated from both the biopsy specimens and peripheral
blood of patients with OLP and showed a well effect (48,
49). Moreover, pre-treated with IL-2, TIMC from OLP
lesions generated more IL-6 than PBMC (6). Taken
together, these results suggested that the IL-2/IL-2R signal
is activated in the OLP lesions, which may play a regulatory
role on the expansion and activation of inltrated T cells in
the OLP lesions.
The regulation of IL-2/IL-2R signal in OLP was also
explored. An early study showed that cyclosporine therapy
leaded to a decrease in the number of IL-2R+-activated
cells, while we and Du et al. recently revealed the negative
regulatory role of B7-H1/PD-1 pathway to the production of
IL-2 in T cells from patients with OLP, suggesting that the
IL-2/IL-2R signal is regulatable and may be a therapeutic
target in treatment for OLP (5052).
To date, the data on IL-2 in the peripheral blood from
OLP are inconsistent. While our group found an elevated
level of IL-2 in the serum of patients with OLP with the
detection of ELISA, Pekiner et al. observed a signicant
decrease in the serum levels of IL-2 in patients with OLP by
the method of bead-based cytokine measurement (19, 20).
In addition, no statistical difference was reported in the
number of IL-2-secreting peripheral blood T cells, which
were detected with an ELISPOT assay (21). The discrep-
ancy of these results may be attributed to the differences of
research mediums and the measurement techniques. Thus,
more unied research strategies may be helpful to better
understand the available controversial results.
IL-4
Characteristics
IL-4 is the representative cytokine of Th2 cells and can
induce the differentiation of nave Th cells to Th2 cells (53).
The cells which initially produce IL-4 to induce Th2
differentiation have not been identied (54). However, once
activated by IL-4, Th2 cells subsequently produce more
IL-4, forming an autocrine positive feedback loop to
maintain their differentiation (54). Besides Th2, Th1 and
mast cells are also the sources of IL-4 (54, 55).
Biological functions
IL-4 has pleiotropic effects on various cell types including T
cells, B cells, macrophages, mast cells, broblasts, endothe-
lial cells, osteoblasts and keratinocytes (56). Its essential
biological role is to drive the differentiation of Th2 cells,
leading to the release of IL-4 and other Th2-type cytokines
such as IL-5 and IL-13 (55). Meanwhile, it can suppress Th1-
and Th17-mediated inammation by inhibiting the produc-
tion of TNF-a, IFN-c, IL-17 (57, 58). Moreover, IL-4 can
promote the proliferation and differentiation of B cells and
upregulate the expression of MHC class II, CD23 and IL-4R
on B cells.
IL-4 in OLP
The expression patterns of IL-4 in OLP have been extensively
investigated. However, the results are inconsistent. Isolated
J Oral Pathol Med
 Cytokines in oral lichen planus
Lu et al.
4
TIMC from the OLP tissue specimen showed an increased
number of IL-4-producing cells compared with TIMC from
inammatory and normal gingival (6). In addition, IL-4
protein and mRNA levels in erythematous/ulcerated OLP
lesions were signicantly higher than normal oral mucosa
(11, 18). However, some investigators reported that IL-4
secretion was not detected from unstimulated OLP lesional T
cells, and IL-4 mRNA was only detected in one of seven
cultured T-cell lines from OLP lesions (9, 10).
Data on saliva and serum IL-4 level in patients with OLP
are also inconsistent. Liu et al. reported an elevated level of
IL-4 in whole unstimulated saliva (WUS) from patients with
OLP, especially in the erythematous/ulcerative subtype.
However, Tao et al. observed no difference in the saliva
IL-4 level between patients with OLP and controls (11, 59).
On the other hand, while we recently found reduced serum
IL-4 level in patients with OLP compared with the healthy
controls (52), others reported higher or comparable levels of
this cytokine in serum from patients with OLP (20, 60). The
reason for these disparities is still needed to be claried in
the future work.
Two studies investigated the gene polymorphism of IL-4
in OLP. Although no difference between the patient with
OLP and control groups in frequencies of both the IL-4
allele and genotype was found, the frequencies of the IL-4
590 C/C genotype in patients with non-erosive OLP were
signicantly higher than the control group (39, 61). In
addition, it is noted that the frequency of the genotype G/G
of the IL-4 1098 was more than sixfold higher in OLP
than in controls (39). These results suggested a possible
relationship between the gene polymorphism of IL-4 and the
susceptibility of OLP, which need further identications.
IL-5
Characteristics
In human, the IL-5 gene is located on chromosome 5 in
close proximity to the gene-encoding IL-4 (62). Although
IL-5 is often considered to be a Th2-specic cytokine, it can
also produced by various other cells types including CD34+
progenitor cells, eosinophils, basophils, mast cells and
gamma delta T cells (cd T cell) (62). The expression of IL-5
is regulated by several transcription factors such as GATA3
(62).
Biological functions
IL-5 is a main regulator of the eosinophil biology including
their differentiation and maturation in the bone marrow,
migration to tissue sites, survival, proliferation and function
in various tissues (63). In addition, IL-5 also appears to play
roles in triggering the terminal differentiation of activated B
cells into antibody-secreting plasma cells (63).
IL-5 in OLP
Evidence for IL-5 in the pathogenesis of OLP is relative
limited. Increased mRNA expression of IL-5 was observed
in OLP lesions compared with normal oral mucosa (18, 22).
On the other hand, although Gotoh et al. found an elevated
mRNA expression of IL-5 in PBMC from patients with
OLP, Kalogerakou et al. reported decreased number of
IL-5-secreting cells in PBMCs from patients with OLP (21,
J Oral Pathol Med
22). Further, Pekiner et al. (20) found no statistical differ-
ences in the serum levels of IL-5 between patients with OLP
and controls. Possible explanations of these inconsistent
results include the diversity sources of IL-5 and the different
composition of subjects involved in these studies.
IL-6
Characteristics
IL-6 is mainly produced by antigen-presenting cells (APCs)
including dendritic cells (DCs), macrophages and B cells
but is also expressed by a variety of non-immune cells such
as keratinocytes, broblasts, epithelial cells, endothelial
cells and astrocytes (64, 65). IL-6 stimulates target cells via
the IL-6 receptor (IL-6R). However, only a few cells express
membrane bound IL-6R, while nearly all cells display
gp130 on the cell membrane, a signalling receptor protein
associated with ligand binding. When cells only express
gp130, they do not respond to IL-6 solely, but can respond
to a complex which is composed of IL-6 and a soluble form
of the IL-6R. In this way, generation of soluble form of the
IL-6R can dramatically enlarge the spectrum of IL-6 target
cells (66).
Biological functions
IL-6 has a broad range of biological activities in immune
regulation, inammation, haematopoiesis and oncogenesis.
Although initially cloned as actors that promote plasma cell
differentiation and antibody production of B cells, IL-6 also
has a profound regulatory role on CD4+ T cells (67). IL-6
has an anti-apoptotic property to CD4+ T cells and can
prolong their survival in vitro by retaining Bcl-2 expression
in the isolated T cells (65). In the Th1/Th2 decision, IL-6
can promote early IL-4 expression and render CD4+ T cells
unresponsive to IFN-c signals, by which to drive Th2
differentiation (65). Furthermore, IL-6 is required for the
differentiation of Th17 from nave CD4+ T cells and
overcomes Treg-mediated immune suppression (65). With
these functions, IL-6 has a pivotal role in switching the
immune response from a tolerant state to active inamma-
tory conditions.
IL-6 in OLP
A number of studies have reported elevated levels of IL-6 in
local and systemic environment of OLP, especially the
erosive forms. Increased IL-6 levels were not only found in
the lesional tissues (68), but also in different oral uids,
such as WUS, saliva-NaCl and lesion TT from patients with
OLP (5, 3537, 69, 70). In addition, saliva IL-6 concentra-
tions were suggested to be useful tools to monitor the
disease activities and therapeutic responses, and to reect in
part the potential of malignant transformation of OLP (36,
37). The reason why the lesional tissues and saliva from
patients with OLP contain higher IL-6 levels may be
explained with the fact that various cell types within the
local microenvironment of OLP could produce signicant
amounts of IL-6, including inltrating monocytes and T
lymphocytes, macrophages, as well as altered keratinocytes.
This viewpoint is supported by the ndings that IL-6 mRNA
was located in inltrating CD4+ and CD8+ T lymphocytes,
as well as basal and suprabasal keratinocytes in OLP lesions

(71). In a series of tissue culture studies, Yamamoto et al.
demonstrated that keratinocytes from OLP lesional tissues
produced much more IL-6 compared with normal and
inamed gingival keratinocytes (6, 34). In addition, TIMC
in OLP tissues also generated more IL-6 than TIMC from
the inammatory gingival and PBMC from patients with
OLP. On the other hand, in patients with OLP, TIMC were
superior to PBMC in the generation of TNF-a and GM-CSF
by the stimulation of IL-6 (6, 34). Taken together, these
ndings suggested that IL-6 is an important inammatory
mediator in the crosstalk between the inltrating lympho-
cytes and altered keratinocytes, resulting in the higher
production of pro-inammatory cytokines and enhance the
local inammatory response in OLP lesions.
Besides the local environment, elevated serum concen-
trations of IL-6 in patients with OLP were also reported (68,
72, 73). In addition, serum IL-6 levels in erosive form of
OLP were signicantly greater than the non-erosive form
(68). Furthermore, investigators also found that the serum
IL-6 levels in patients with OLP were decreased after a
certain kinds of therapies, such as levamisole and Chinese
medical herbs (73). These ndings suggested that serum IL-
6 level may be a useful marker in evaluating the disease
activities of OLP and the therapeutic effects of some
medicines. Unlike its serum levels, the expression of IL-6 in
the PBMC from patients with OLP was decreased or
showed no difference than the controls, which may be
attributed to the suppressed immune function of PBMC
from patients with OLP (21, 72).
Xavier et al. investigated gene polymorphism of IL-6 in a
cohort of Brazilian patients with OLP and found a
signicant higher frequency of IL-6 174 G/G genotype
in patients with OLP and associated with the susceptibility
of OLP, suggesting the involvement of the IL-6 gene
polymorphisms in the genetic basis of this disease (25).
IL-8
Characteristics
IL-8, also known as CXCL8, was rst cloned as a neutrophil
chemotactic factor from LPS-stimulated human mononu-
clear cell supernatants (74). IL-8 can be produced by various
immune cells, such as monocytes, T cells, neutrophils and
NK cells, and non-immune somatic cells, such as endothe-
lial cells, broblasts, and epithelial cells and broblasts (75).
IL-8 production is not constitutive but inducible by pro-
inammatory cytokines, such as IL-1b, TNF-a and IL-17,
microbial products and cellular stress (75). On the other
hand, other molecules, such as IL-4 and TGF-b, and some
natural agents, such as lycopene and green tea, would inhibit
the synthesis of IL-8 (76, 77).
Biological functions
IL-8 is an important mediator of host response to injury and
inammation. IL-8 can promote the plastic of neutrophils,
their adhesion to endothelial monolayers and transendothe-
lial migration (75). Moreover, IL-8 can activate various
functions of neutrophils including degranulation, respiratory
bust and releasing of defensins and matrix metal proteinases
(MMPs) (78). IL-8 is also chemotactic for many other types
of migratory immune cells such as macrophage, basophils
Cytokines in oral lichen planus
Lu et al.
5
and T cells by increasing the chemotaxis and the expression
of adhesion molecules (75). In addition, IL-8 enhances the
metabolism of reactive oxygen species (ROS) and supports
mitosis of epithelial cells and angiogenesis, therefore may
play a role in disorders such as rheumatoid arthritis and
various tumours (79).
IL-8 in OLP
Although IL-8 was not detected in the oral mucosal cells of
OLP lesions, many studies have consistently shown
elevated levels of IL-8 in serum and oral uids from
patients with OLP (5, 3537, 70, 80, 81). This disparity
between the lesional tissues and systematic uid indicates
that IL-8 may mainly function in the systematic immune
response of patients with OLP rather than in the local
lesions. In addition, because the abnormal serum level of
IL-8 level can detect in more patients with OLP than the
serum IL-6 level, Sun et al. (81) concluded that serum IL-8
level is a more sensitive marker than serum IL-6 level in
monitoring the disease activity and the therapeutic effects
of OLP.
In a study with ethnic Chinese cohort, Zhang et al. (70)
showed that the saliva concentrations of NF-rB-dependent
cytokines from patients with OLP were much higher than
their levels in serum, among which IL-8 was the most
outstanding one. The authors also found that IL-8 salivary
levels tended to change from reticular to erosive form of
OLP, suggesting that the salivary assay for IL-8 may be one
of the promising biomarkers for OLP severity (70).
Similarly, Rhodus et al. observed increased IL-8 level in
different oral uids from OLP, and the salivary levels of IL-
8 were decreased signicantly following the dexamethasone
treatment and signicantly correlate with the VAS score,
indicating that salivary analysis of IL-8 may be applied to
monitoring the therapeutic response of OLP (5, 35, 36). In
addition, they found signicantly lower level of salivary
IL-8 in OLP with epithelial dysplasia than patients with
OSCC, indicating that salivary IL-8 level may be a useful,
non-invasive method for monitoring malignant transforma-
tion of OLP (37).
Recently, Dan et al. investigated the association of gene
polymorphisms of IL-8 with OLP in a Chinese population
and found signicantly lower frequency of the 251 AA
genotype in the erosive OLP group than the controls.
Haplotype analysis revealed decreased frequency of the
251 A/+781 C haplotype and increased frequency of the
251 T/+781 C haplotype in patients with erosive OLP
when compared to healthy controls, suggesting that the IL-8
gene polymorphisms may be associated with the severity of
OLP (82).
IL-10
Characteristics
IL-10 is initially described as a secreted cytokine synthesis
inhibitor factor (CSIF) from Th2 clones for its inhibitory
effect on the production of IL-2 and IFN-c in Th1 cells, but
it is now known as a much more broadly expressed cytokine
(83). Although primarily produced by monocytes,
macrophages and CD4+Th cells, IL-10 can also synthesize
by almost all cell types in immune system (84, 85). In
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 Cytokines in oral lichen planus
Lu et al.

6
CD4+Th cells, production of IL-10 is accompanied by the found difference in frequencies of IL-10 alleles and
expression of specic cytokines which are required for the genotypes between the patients with OLP and healthy
development of each subset lineage. However, the expres- controls, Bai et al. (88) revealed that the 1082A/ 819T/
sions of these cytokines are downregulated by IL-10, 592A haplotype of the IL-10 polymorphisms, which
indicating its role in a negative feedback loop which limits correlated with a lower serum level of IL-10, had a
the immune responses (84). In monocytes and macrophages, signicant association with OLP, suggesting that IL-10
IL-10 is synthesized in response to various endogenous and gene polymorphisms may have some inuence on the
exogenous mediators such as bacterial LPS and catechol- disease susceptibility and progression of OLP.
amines (84).
IL-12
Biological functions
Characteristics
As an anti-inammatory cytokine, IL-10 exhibits diverse
Initially known as natural killing-stimulating factor and
functions to different target cells. In monocytes/macro-
cytotoxic lymphocyte maturation factor, IL-12 was iden-
phages, which are the main target cells of IL-10, it can
tied as a heterodimeric cytokine composed of two
suppress the release of pro-inammatory cytokines and
covalently linked p35 and p40 subunits (89). IL-12 is
functions of antigen presentation, but enhance the phago-
produced mainly by monocytes, macrophages, DCs and B
cytosis effect (84). IL-10 also inhibits both the prolifer-
cells, and to a less extent by activated T cells (90). The
ation and the cytokine synthesis of Th1 and Th2, and
production of IL-12 requires specic priming signals from
causes CD4+ T cells to develop a regulatory phenotype
bacterial products and amplication signals from cyto-
(84). However, IL-10 has no direct inhibitory inuence on
kines produced by T cells or DCs. On the contrary,
Th17 or CD8+ T cells (84). Similarly, IL-10 inhibits the
cytokines such as IL-10 and TGF-b can negatively regulate
release of pro-inammatory mediators by neutrophils and
IL-12 production (89).
the secretion of chemokines to attract neutrophils (84). It
is notably that IL-10 also has non-inhibitory functions on
Biological functions
several immune cells. For instance, it can enhance the
The major functions of IL-12 include induction of IFN-c
proliferation, differentiation and MHC expression of B
production by NK cells and T cells, increasing the NK cell
cells. Moreover, it also stimulates the cytotoxic activity of
cytotoxicity and T-cell proliferation (89, 90). It also can
NK cells (84).
boost the effects of cytotoxic T cells by inducing the
production of cytolytic factors including perforin and
IL-10 in OLP
granzymes (89). More importantly, produced by macro-
It was observed that TIMC from OLP generated more IL-10
phages or DCs in response to microbial pathogens, IL-12
than those from the gingiva and peripheral blood mononu-
was a key cytokine in differentiation of nave T cells into
clear cells, and IL-4-pre-treated TIMC from the patients
Th1 lineage, indicating its central role in a pathway by
released a larger amount of IL-10 (6). Positive hybridization
which innate immune cells drove the adaptive immune
signals for IL-10 in mononuclear cells near the basement
response (89). Therefore, IL-12 is required for the resistance
membrane and within the inltrate in OLP lesions were also
to bacterial and intracellular parasites, and the establishment
observed (9). Positive signals for IL-10 mRNA were also
of organ-specic autoimmunity (90).
found in six from seven of the T-cell lines isolated from
OLP lesions (9). Thus, IL-10 was once considered as a
IL-12 in OLP
critical member of the local cytokine network in microen-
Studies on IL-12 in OLP are limited. Ohno et al. (87) found
vironment of OLP. However, this viewpoint was challenged
higher amounts of IL-12 produced in the peripheral blood
by the observation by Khan et al. (10) that IL-10 secretion
monocytes from patients with OLP than healthy controls.
was not detected in OLP lesional T cells, making this
Further studies demonstrated that the salivary epithelial cells
situation more complicated.
from OLP subjects secreted elevated level of IL-12 (91).
Several studies also revealed the levels or productions of
The increased expression of IL-12 was always companied
IL-10 in peripheral blood, but the results were inconsistent.
by the highly expression of TLRs (87, 91). In contrast,
In a recently work of our group, we found a decreased
Kalogerakou et al. (21) reported decreased number of IL-
tendency of serum IL-10 levels in patients with OLP, but
12-secreting T cells in the peripheral blood of patients with
Pekiner et al. and Dan et al. observed increased IL-10 levels
OLP. These results suggested that monocytes and epithelial
in serum from patients with OLP (20, 52, 86). In addition, in
cells are likely the major sources of IL-12 in OLP, and its
another two studies, the investigators observed signicantly
expression may depends on, at least in part, the expression
decreased abilities of peripheral blood T cells and mono-
pattern of TLRs in different cells. Considering the character
cytes from patients with OLP to produce IL-10 in vitro (21,
of this cytokine, IL-12 may act as the promoter, but not the
87). The reason for the inconsistency remains unclear,
effector in the Th1 immune response in both local
however, some investigators speculated that the diversity of
environment and peripheral blood of OLP.
IL-10 expression patterns in patients with OLP may due to
difference regulatory mechanisms, including the induction
effects from other inammatory mediators and the various IL-17
genetic tendency of this disease (86, 87). Characteristics
Two studies concerned with the IL-10 gene polymor- Originally cloned from a rodent T-cell hybridoma, IL-17
phisms in OLP population (25, 88). Although neither study (also known as IL-17A) is the founding member of IL-17

J Oral Pathol Med


cytokine family (92). Structurally, IL-17 is a homodimeric
glycoprotein of 155 amino acids sequence which exhibits
high homology to HVS13, an open reading frame of the T
lymphotropic rhadinovirus Herpesvirus saimiri (93). IL-17
is primarily secreted from T cells, but also by various other
cell types including dendritic cells, macrophages, natural
killer cells and cd-T cells (94). IL-17 was also shown as the
dening cytokine of a novel class of T-helper cell subsets
termed Th17, which is distinct from Th1 and Th2 (95).
Biological functions
IL-17 has emerged as a central player in the immune system.
Although produced primarily by T cells from the adaptive
immunity, IL-17 also plays a crucial role in innate immunity
by triggering the production of numerous chemokines,
resulting in the recruitment of neutrophil and macrophage to
clear pathogens (96). Thus, IL-17 is considered as an
important bridging molecular between the adaptive and
innate immunity (96). In addition, IL-17 has pleiotropic
effects on different tissue cells and immune cells. It was
demonstrated that IL-17 stimulates the production of various
inammatory mediators such as TNF-a, IL-1b, IL-6, IL-8,
MCP-1, GM-CSF and matrix metalloproteases (MMP) in
monocytes, epithelial cells, endothelial cells, keratinocytes
and broblasts (94). In this way, IL-17, together with its
down-stream molecules, is involved in the formation and
maintenance of the local inammatory microenvironment
(94).
IL-17 in OLP
The exploration of IL-17 in OLP is just at its beginning. In a
DNA microarray study, IL-17A gene was identied to be
up-regulated by over sevenfold in OLP lesions compared
with the normal oral mucosa (97). Subsequently, IL-
17+CD4+T cells, termed as Th17 cells, were found to
present in OLP lesions, especially in atrophicerosive form
(98). In addition, a recent study showed increased mRNA
levels of IL-17 in both biopsies of erosive OLP lesions and
inltrated CD4+T-cell clones from erosive OLP lesions
(18). Although the serum IL-17 levels in patients with OLP
compared with healthy controls are inconsistent, the com-
bination of OLP and chronic periodontitis was apparently
linked to the elevated serum levels of IL-17 (98, 99). These
ndings suggested a potential role of IL-17 in the local
inammatory environment of OLP lesions, rather than the
systemic immune status of the patients, but the specic role
of this important cytokine in the OLP pathogenesis is still
unknown.
IL-18
Characteristics
IL-18 was originally identied as IFN-c-inducing factor
(IGIF) for its powerful inducing function on IFN-c produc-
tion by T cells and NK cells (100). IL-18 is mainly produced
by macrophages and immature DCs during the acute
immune responses, but is also by various immune and
non-immune cells, including T cells, B cells, epithelial cells,
adrenal cortex cells, astrocytes and keratinocytes (101).
Lacking a classical signal sequence necessary for secretion,
IL-18 is initially synthesized as a 24 kDa biologically
Cytokines in oral lichen planus
Lu et al.
7
inactive precursor and requires the cleavage by caspase-1
dependent or independent manners to process into an 18-
kDa bioactive molecule (102).
Biological functions
IL-18 is a pleiotropic cytokine in inammation and
autoimmunity, which can support the differentiation and
activation of different Th-cell subsets depending on its
surrounding cytokine milieu (102). Synergizing with IL-12,
IL-18 displays powerful ability to induce the production of
IFN-c by NK cells and T cells and to drive Th1-cell
development. However, in the absence of IL-12, IL-18
changes to support the Th2 differentiation via inducing NK
and T cells to produce Th2-type cytokine such as IL-4, IL-5,
IL-10 and IL-13 (102). Thus, IL-18 seems as a balance
factor between the Th1 and Th2 immune response and plays
a pivotal role in the modulation of the immune status (102).
IL-18 is also involved in the recruitment of DCs to the site
of inammation and the maturation process of myeloid
DCs, indicating its ability to mediate adaptive immune
responses (102). Additionally, IL-18 can activate many cell
types which are the sources of IL-18 in an autocrine manner,
indicating its important role in the sustaining of many
chronic inammatory pathologies (100). It has been found
that elevated serum levels of IL-18 were associated with
disease severity and poor clinical outcomes of many
inammatory and autoimmune disorders (101).
IL-18 in OLP
Although the mechanisms of IL-18 activity in many other
inammatory and autoimmune disorders have been widely
explored, to date, there are only a few studies concerning
IL-18 in OLP. The mRNA expression of IL-18 has no
difference between the OLP lesion and normal oral mucosa,
but signicant elevated levels of IL-18 protein in both the
serum and saliva from patients with OLP had been shown
(18, 23). In addition, the concentrations of IL-18 in serum
and saliva from patients were positive correlated with the
severity of illness, indicating its values in predicting the
prognosis of the disease (23). On the other hand, in the view
of genetics, data revealed a signicant difference in IL-18
607 genotype distributions between the patients and the
controls (103). Further and notably, the identied polymor-
phisms at the IL-18 promoter region (i.e. -137G/G) appear
to be statistically associated with the more severe erosive
subtype and exert positive effect on the production of IL-18
protein in serum from patients with OLP, suggesting that the
up-regulation of IL-18 production in the patients body may
have its genetic background, which maybe involved in the
pathogenesis of OLP (103).
Transforming growth factor-b
Characteristics
Transforming growth factor-b (TGF-b) is a member of a
superfamily of structurally related growth and differentia-
tion factors, and is conserved through evolution and found
almost in all multicellular organisms (104). There are three
highly homologous isoforms of TGF-b exist in humans:
TGF-b1, TGF-b2 and TGF-b3, which share a receptor
complex and signalling pathways but express differently
J Oral Pathol Med
 Cytokines in oral lichen planus
Lu et al.

8
depending on the tissues (105). Initially, all TGF-b ligands acts as an inducer of the epithelialmesenchymal transition
are synthesized as inactive precursors. After dimerization, (EMT), a signicant step in malignant transformation (106).
TGF-b precursors are cleaved by proteases and interacted Therefore, the TGF-b may play an important role in the
with latency-associated peptides (LAPs) into small latent cancerization of OLP, but the underlying mechanisms are
complexes (SLP), which then are transported to extracellular still unclear.
matrix (ECM) where further bind to latent TGF-b-binding Data on the serum level of TGF-b in patients with OLP
proteins (LTBPs) to form large latent complexes (LLC). The are inconsistent. Zhou et al. observed slightly increased
TGF-b activation process included the release of LCC from serum levels of TGF-b1 in patients with OLP, while
ECM by proteases, followed by proteolysis of LAPs and Taghavi Zenouz et al. recently reported a signicant
LTBPs to release active TGF-b dimmers, which is capable decrease in the serum levels of TGF-b in patients with
of signalling (104, 106). OLP (111, 112).
In addition, in a study concerning the cytokine gene
Biological functions polymorphism in OLP, no signicant difference in the allele
The most potent functions of TGF-b are the growth or genotype frequencies of TGF-b were observed between
inhibition and apoptosis induction of many cell types, the OLP subjects and healthy controls (39).
including epithelial, endothelial, broblastic, haematopoiet-
ic and immune cells (104, 105). TGF-b also has marked
Interferon-c
effect on the ECM composition, angiogenesis and induction
Characteristics
of epithelialmesenchymal transition (EMT), thus is possi-
Interferon-c (IFN-c) is the only type II interferon and is the
bly responsible for many physiological and pathological
lineage-specic cytokine of Th1 cells (113). Initially, IFN-c
features in the mesenchyme (104, 105).
was thought to be exclusively produced by CD4+Th cells,
TGF-b is an important immune-suppressing cytokine
CD8+T cytotoxic cells and NK cells, but later evidence
which has broad effects on most immune cells. In adaptive
demonstrated that some other cells, such as B cells, APCs
immune system, TGF-b can repress T-cell proliferation and
and NK T cells, are also the sources of IFN-c (113). IFN-c
induce the apoptosis of B cells, in which way to suppress
is produced by these cells only when activated by some
the immune responses (104). Moreover, TGF-b can sup-
other cytokines, especially IL-2, IL-12 and IL-18. On the
press the inammatory Th1 and Th2 cell differentiation and
contrary, the IFN-c production is negative modulated by IL-
induce the development of Tregs, which are crucial for the
4, IL-10, TGF-b, glucocorticoids and cyclosporin A (113).
maintenance of immune tolerance (104). With respect to
innate immune system, TGF-b can repress the IFN-c
Biological functions
production by NK cells and also polarize the pro-inam-
IFN-c is one of the most critical mediators of immunity and
matory type macrophage (M1) to the anti-inammatory type
inammation. IFN-c has been long appreciated to the
phenotype (M2) (104). The regulatory roles of TGF-b in
promotion of innate immune responses by activating
immune system are highly complex and context dependent,
macrophages (114). IFN-c also up-regulates various pro-
in which many molecule details are involved.
inammatory mediators by disrupting several anti-inam-
matory feedback loops (114). In addition, IFN-c directly
TGF-b in OLP
inhibits the expressions and the downstream signalling
Although the mRNA expression of TGF-b1 has been
pathways of anti-inammatory molecules, which represents
identied in all the OLP biopsies studied, the immunosta-
important mechanisms of IFN-c-mediated innate immune
inings of TGF-b1 were variable in the subepithelial inltrate
responses (114). As a major effector cytokine of Th1 cells,
of the OLP lesions (9, 10). Moreover, TGF-b1 secretion was
IFN-c autoamplies Th1 responses by activating NK cells
not detected in any OLP lesional T-cell lines in vitro (10).
and macrophages, as well as promoting the specic
Additionally, over-expression of Smad7 (inhibitor of TGF-b
cytotoxic immunity via T cell and APC interaction (115).
signalling), together with reduced expressions of phosphor-
On the other hand, IFN-c inhibits the differentiations and
ylated Smad2/3 (pSmad2/3) and Smad4 (activators of TGF-
functions of other Th-cell subsets such as Th2 and Th17
b signalling), has been observed in erythematous OLP
(116, 117), by which mechanisms it can maintain the Th1
lesions (107). These ndings suggested that the immuno-
lineage commitment and phenotype stability. In addition,
suppressive TGF-b pathway is inhibited in the lymphocytic
IFN-c exerts functions to limit tissue damage in the
inltrations in OLP lesions, which may contribute to the
inammation site and inhibit the proliferation of various
chronic inammation of OLP (105). The inhibition of TGF-
cell types (114). Accumulated evidence has supported both
b pathway in the T cells from OLP may be attributed, in
the promoting and suppressive roles of IFN-c in various
part, to the over productions of IFN-c, which blocks the
inammatory and autoimmune diseases (114, 118).
phosphorylation of Smad3 (105). Thus, the balance between
TGF-b and IFN-c signalling may determine the immuno-
IFN-c in OLP
logical activities in OLP lesions and may be a therapeutic
OLP is a T-cell-mediated chronic inammatory disease in
target (108).
which Th1 is considered to play a predominant role (3, 10,
Several recent studies have identied that the expressions
11). As the specic cytokine of Th1 cells, IFN-c has been
of TGF-b1 were signicant elevated in the malignantly
one of the most extensively studied cytokines in OLP. In
transformed cases of OLP (109, 110). It has been known
early studies, positive staining of IFN-c at both mRNA and
that TGF-b probably inhibits growth in the early stages but
protein levels have been observed in mononuclear cells
promotes growth at the later stages of tumorigenesis and

J Oral Pathol Med


throughout the subepithelial inltrate in the OLP lesions
(10, 119). Meanwhile, strong messages of IFN-c have also
been found in the isolated T-cell lines from the OLP
biopsies (10, 18). Recently, the expressions of IFN-c have
also been located on the CD4+Th cells in OLP lesions (98).
Additionally, the expression levels of IFN-c in erosive OLP
lesions, but not reticular OLP lesions, have been reported to
be elevated compared with normal oral mucosa (11, 18). It
has been speculated that the over-expression of IFN-c may
be involved in the activation of CD8+ T cells and maintains
the expression of major histocompatibility class on the
keratinocyte at the advanced stage of OLP development (3).
The elevated expressions of IFN-c in OLP lesions may have
clinical signicance, for the number of IFN-c-positive
mononuclear cells in OLP lesions decreased after the
treatment of 0.1% uocinolone acetonide for 1 month,
indicating an association between the IFN-c expression and
the clinical manifestation of OLP lesions (120).
The data on the salivary IFN-c level in patients with OLP
were inconsistent. Liu et al. (59) observed a signicantly
lower level of salivary IFN-c in patients with OLP.
However, Tao et al. reported that salivary IFN-c level in
erythematous or ulcerated patients with OLP was signi-
cantly higher than that in reticular OLP and control group
(11). In addition, Ghallab et al. (121) found elevated level
of salivary IFN-c in erosive patients with OLP, which could
be decreased signicantly after treatment with prednisone.
The reason of the disparity is still unclear.
Although the level of IFN-c is increased in the local lesion
of OLP, its production in the PBMCs from patients with OLP
exerts an suppressed status. Several studies consistently
reveal that the productions of IFN-c in the PBMCs from
patients with OLP were reduced compared with those from
healthy donors, either spontaneous or with other stimulus
such as IL-2, phytohemagglutinin (PHA) or puried protein
derivative (PPD) (21, 60, 122, 123). These data indicated that
the peripheral cellular immunosuppression may be a hallmark
of OLP. On the other hand, data on the serum levels of IFN-c
were inconsistent. We reported an increased serum level of
IFN-c in patients with OLP (19), but other investigators found
no statistical differences in the serum levels of IFN-c between
patients with OLP and controls (20, 124), The discrepancy of
these results may due to some other sources of IFN-c
production, except for PBMCs, in the peripheral blood, but
further identications are still needed.
As IFN-c is a predominant cytokine in the pathogenesis
of OLP, the inuence of gene polymorphism of IFN-c on
the susceptibility of OLP was investigated (24, 27, 39, 61).
To date, two genotype polymorphisms in the rst intron of
the promoter of IFN-c gene, UTR 5644 T/T genotype and
+874 T/T genotype, have been found to have higher
frequencies in patients with OLP and associated with the
susceptibility, suggesting the genetic polymorphism of IFN-
c may be a risk factor to OLP development.
Tumour necrosis factor-a
Characteristics
Tumour necrosis factor-a (TNF-a) was rst identied as an
endotoxin-induced glycoprotein, which caused haemorrhag-
ic necrosis of sarcomas (124). TNF-a is mainly produced by
Cytokines in oral lichen planus
Lu et al.
9
activated macrophages and T cells, but also by a wide range
of cell types including immune cells (B cells, dendritic cells,
NK cells, master cells and neutrophils), non-immune cells
(keratinocyte, broblasts, astrocytes and glial cells) and
various tumour cells (125). TNF-a is rstly produced as a
26-kDa precursor (also known as transmembrane TNF,
tmTNF-a), which is expressed and bound on the membrane
of cells, where it can be cleaved by the TNF-a-converting
enzyme in the extracellular matrix, leading to the releasing
of a 17-kDa soluble TNF-a (124). Both the transmembrane
and soluble forms of TNF-a are active, but have distinct
biological activities (124).
Biological functions
TNF-a is not detectable in healthy individuals, but is rapidly
released after trauma, infection or exposure to pathogen
stimulus and become one of the most abundant early
mediators in inamed tissue (126). TNF-a is a key regulator
of innate immunity and almost always enhances innate
immune responses. It plays a signicant role in maturation
of DCs and can activate the migration and phagocytosis of
macrophage, both of which are the main source of TNF-a
(126, 127). This forward feedback loop may be an important
in maintaining the innate immune responses. TNF-a also
plays important roles in adaptive immunity. The effects of
TNF-a on T cells are depending on the exposure periods
(128). Short-term stimulation of TNF-a results in prolifer-
ation and activation of T cells. However, long-term TNF-a
exposure induces a reversible loss of surface T-cell receptor
complex, leading to hyporesponsiveness of T cells, without
affecting the IL-2-mediated cell proliferation (128). More-
over, TNF-a can amplied the Th1 response by inducing the
productions of IL-12 and IL-18, which are potent inducers
of IFN-c (129). In addition, TNF-a promotes the growth and
activities of B cells and inducing the production of IL-1 and
IL-6. Reversely, B cells can produce amounts of TNF-a in
an autocrine loop (128).
Notably, TNF-a appears to be a potent modulator of
cellular apoptosis by binding to a TNFR-associated death
domain through the TNFR1 in various cell types. This
function occurs not only during normal development but
also in pathogenic conditions with an increased TNF-a
production (129).
TNF-a in OLP
Compared with other cytokines, TNF-a is obviously the
most extensively studied cytokine in OLP. Over productions
of TNF-a have been consistently observed in the OLP
lesions in comparison with the non-lesional or normal oral
mucosa (130133). Moreover, the elevated expression of
TNF-a in OLP lesion could be inhibited by topical steroid
such as 0.1% uocinolone acetonide in orabase, indicating
that the over-expression of TNF-a may be associated with
the immunopathogenesis of OLP (133). Different cell types,
including keratinocytes, mast cells and CD4+T cells, have
been identied as the sources of TNF-a in the OLP lesions
and exert hyperactivities in the TNF-a production (6, 810,
34, 130133). Compared with the keratinocytes from
chronically inamed and non-inamed gingiva, keratino-
cytes from OLP lesions produced much more TNF-a (6,
J Oral Pathol Med
 Cytokines in oral lichen planus
Lu et al.
10
34). Similar results were also seen in tissue-inltrating
CD4+T cells from OLP lesions, which produced much more
TNF-a than their counterparts from healthy oral mucosa (6,
18, 34). In addition, hyperproduction of TNF-a was also
found in the degranulated mast cells in OLP lesions (134).
The elevated level of TNF-a in OLP lesion indicates its
biological activities in the local inamed environment.
Indeed, the TNF receptors were also observed to be
expressed by the mononuclear cells and epithelial keratino-
cytes in OLP lesions (130). Furthermore, previous studies
have found that TNF-a stimulation induced the production
of various inammatory mediators such as RANTES,
MMP-9 and TNF-a itself, indicating that TNF-a in OLP
lesion is truly functional (10, 134, 135). Considering its
pivotal roles in the immune regulation, TNF-a has also been
proposed to be involved in several other processes including
apoptosis of basal epithelial cells and the activation of
Langerhans cells, which are the typical hallmarks of OLP
lesions, but the relevant evidence is still needed (3, 136).
Many authors consistently observed increased salivary
levels of TNF-a in patients with OLP (3537, 70, 121, 137).
Moreover, the elevated levels of TNF-a in saliva from
patients with OLP were decreased to the normal levels after
treatment with glucocorticoids such as prednisone and
dexamethasone, suggesting the possibility of applying
salivary TNF-a level to monitor the disease activity and
therapeutic effects of OLP (36, 121).
Most studies consistently observed elevated levels of TNF-
a in the serum from patients with OLP when measuring with
an ELISA method (72, 111, 138141). However, using a
bead-based cytokine measurement, Pekiner et al. (20) found
no statistical difference in the serum levels of TNF-a between
patients with OLP and controls. This disparity indicates the
inuence of different detecting methods to the results. Sun
et al. (141) reported that the high serum TNF-a level could be
reduced to a normal level with the treatment of levamisole in
patients with erosive OLP, suggesting that the serum TNF-a
level, like its counterpart in saliva, may also have a value in
evaluation of therapeutic efciency. Although the TNF-a
levels were elevated in the serum from patients with OLP, its
expressions in PBMCs from patients exhibited an inhibitory
status, suggesting impaired function of lymphocytes in
patients (122).
It has been noted that the presence of gene polymorphism
in TNF-a gene, especially a biallelic single-nucleotide
polymorphism at 308 loci in the promoter, is associated
with elevated TNF-a levels and thus increases the suscep-
tibility to a wide variety of human diseases (142). In recent
years, several studies have evaluated the association
between the 308 G/A polymorphism in TNF-a gene and
susceptibility of OLP, but the results were conicting.
Although most authors observed higher frequencies of the A
allele (G/A or A/A genotype) of the TNF-a 308
polymorphism in patient with OLP, whereas other authors
did not nd difference in frequencies of TNF-a alleles and
genotypes between the patients with OLP and healthy
controls (2427, 39, 88). In a meta-analysis study, Jin et al.
(143) carried out a comprehensively evaluate interactions on
TNF-a 308 G/A polymorphism and LP risk and showed
no association between this polymorphism and LP risk in
combined analyses. Moreover, in the subgroup analysis by
J Oral Pathol Med
subtypes of CLP and OLP, ethnicity and HCV infection, the
authors found no signicant connections of risks from CLP
or OLP groups for AA+GA vs. GG comparison, but
signicant increased OLP risks among population with
mixed ethnicity and patients without HCV infection. In
conclusion, the authors stated that the negative results could
have been biased for the lacking of some information of
HCV status and clinical variety in some previous studies
and suggested more studies are needed to validate these
associations (143).
Although TNF-a antagonists have become approved
therapeutic agents in some immune-mediated inammatory
diseases for many years, their off-label use in inammatory
oral mucosal diseases is just at its beginning (144). Several
case reports have demonstrated benet responses to TNF-a
antagonists in patients with OLP those were refractory to
systematic glucocorticoids and immunosuppressants (145
147). These include successful treatment with etanercept in
one case with severe erosive OLP, iniximab in another
case with severe orogenital LP and adalimumab in two
additional cases with severe orogenital LP, revealing the
clinical feasibility of TNF-a antagonist in the treatment for
OLP (146, 147). However, it should be concerned that TNF-
a antagonist may have some side-effects such as headache,
initiating lichenoid reaction, systemic lupus erythematosus-
like disease, inducing viral infection and the risk of
carcinogenesis (147). These potentially adverse events
may be a barrier to the future application of TNF-a
antagonist and should always be noted in the clinical use
(147).
Conclusion and future prospect
Cytokines have broad biological functions which are
relevant to many aspects in immunity and inammation.
Imbalance of cytokine networks has been implicated in the
pathogenesis of various immune-mediated inammatory
diseases. In the context of OLP, it is clear that many
inammation-related cytokines are aberrantly produced by
different cell types both in the local lesions and peripheral
blood, as summarized in the present review. The abnormal
expression pattern of these cytokines is a concrete reection
of the immune dysregulation status and may play a central
role in the onset and development of OLP.
From the current knowledge, although a great progression
has been achieved on the research of cytokine in OLP
pathogenesis in the last two decades, there are still many
aspects in this eld that we do not fully understand. To date,
data on the expression of many cytokines in OLP are
inconsistent. These disparities may attribute to the different
detecting methods, and distinct subjects who are under
unknown classications such as genetic background,
clinical form, lesion site, gender and age. Therefore, further
investigations with optimized experimental approaches and
rening subgroup analysis are required. Besides, it is
becoming increasing clear that cytokines do not work
separately, but interact and function in complex immuno-
modulation networks. It is very likely that perturbations in
cytokine networks determine the progression of OLP.
However, most published data are limited to the expressions
of single or several cytokines OLP, thus do not sufcient to

Lu et al.
explain the complexities of the cytokine network in the
pathogenesis. In addition, knowledge about the intrinsic
mechanisms by which the cytokine networks contribute to
the chronic inammatory environment of OLP are still
lacking. To resolve these problems, future research will
need to be expanded to the interaction between these
cytokines and their regulatory roles in both local or systemic
immune networks, as well as the mechanisms by which they
can synergize or antagonize with each other to inuence the
ongoing inammation in OLP environment. Further inves-
tigation on the aberration of the cytokine network and their
regulatory roles in the onset and development of OLP will
deepen our understanding of the pathogenesis and lead to
the identication of novel and better therapeutic approaches
of this disease.
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Acknowledgement
This work was supported by grants from the National Natural Science
Foundation of China (No. 81170972, 81371147) to Gang Zhou, (81200797)
to Rui Lu and (81000448) to Gefei Du, respectively.
Conflict of interest
The authors declare no conict of interest in this study.