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Cytokine-Mediated Immunopathogenesis of Hepatitis B
Virus Infections
Xuefen Li &Xia Liu &Li Tian &Yu Chen
Published online: 6 December 2014
#Springer Science+Business Media New York 2014
Abstract Hepatitis B virus (HBV) infection is a world-
wide health problem, with approximately one third of
populations have been infected, among which 3–5%of
adults and more than 90 % of children developed to
chronic HBV infection. Host immune factors play essen-
tial roles in the outcome of HBV infection. Thus, ineffec-
tive immune response against HBV may result in persis-
tent virus replications and liver necroinflammations, then
lead to chronic HBV infection, liver cirrhosis, and even
hepatocellular carcinoma. Cytokine balance was shown to
be an important immune characteristic in the development
and progression of hepatitis B, as well as in an effective
antiviral immunity. Large numbers of cytokines are not
only involved in the initiation and regulation of immune
responses but also contributing directly or indirectly to the
inhibition of virus replication. Besides, cytokines initiate
downstream signaling pathway activities by binding to
specific receptors expressed on the target cells and play
important roles in the responses against viral infections
and, therefore, might affect susceptibility to HBV and/or
the natural course of the infection. Since cytokines are the
primary causes of inflammation and mediates liver injury
after HBV infection, we have discussed recent advances
on the roles of various cytokines [including T helper type
1 cells (Th1), Th2, Th17, regulatory T cells (Treg)-related
cytokines] in different phases of HBV infection and
cytokine-related mechanisms for impaired viral control
and liver damage during HBV infection. We then focus
on experimental therapeutic applications of cytokines to
gain a better understanding of this newly emerging aspect
of disease pathogenesis.
Keywords Hepatitis B virus .Cytokine .
Immunopathogenesis .Immunotherapy
Introduction
Hepatitis B virus (HBV) is the most prevalent virus that has
been implicated in causing acute and chronic hepatitis.
Immune-mediated mechanisms have been found to play im-
portant roles in various clinical presentations of HBV infec-
tion. In humans, the rate of chronicity is inversely proportional
to age, such as only 3–5 % of adults infected by HBV
persisting for more than 6 months can lead to chronic infec-
tion, whereas >90 % of children infected with HBV tend to
develop chronic infection [1,2]. Meanwhile, the risks of
developing liver cirrhosis and hepatocellular carcinoma are
greatly enhanced in patients with chronic HBV infection [2,
3]. The differences among host’s immune response can be one
of the reasons for the development and progression of hepa-
titis B [4,5]. Recent years, emerging evidences have sug-
gested that cytokines and regulatory molecules should be
regarded as fundamental mediators in determining the host’s
innate and adaptive immune responses to HBV and viral
clearance, and, therefore, the level of cytokine expression
may play a key role in disease outcome and effective antiviral
immunity (Table 1)[57,58].
Cytokines represent a large family of molecules, including
T helper type 1 cells (Th1)-associated cytokines [e.g., inter-
leukin (IL)-2, interferon (IFN)-γ], which have a functional
contribution to cellular immune responses; T helper type 2
cells (Th2)-associated cytokines(e.g., IL-4, IL-6, IL-10),
which have roles in the humoral immune responses; regulato-
ry T cells (Treg)-associated cytokines [e.g., tumor growth
X. Li :X. Liu :L. Tian :Y. Chen (*)
State Key Laboratory for Diagnosis and Treatment of Infectious
Diseases, First Affiliated Hospital, School of Medicine, Zhejiang
University, 79 Qingchun Road, Hangzhou 310003, People’s
Republic of China
e-mail: zychenyu@126.com
Clinic Rev Allerg Immunol (2016) 50:41–54
DOI 10.1007/s12016-014-8465-4
factor-beta (TGF-β), IL-10], which have been associated with
immunomodulation and immunosuppression; and T helper
type 17 cells (Th17)-associated cytokines (e.g., IL-17, IL-22,
IL-23), which play critical roles in mediating inflammation
[43]. Cytokines initiate downstream signaling pathway activ-
ities by binding to specific receptors expressed on the target
cells and play important roles in the responses against viral
infections and, therefore, might affect susceptibility to HBV
and/or the natural course of the infection [59].
Although many immune cells are able to secrete cytokines,
current information suggests that cytokines are mainly re-
leased by T lymphocytes and macrophages, which play
Tabl e 1 Profiles of cytokines
Cytokine Cell sources Primary effects Effects in HBV infection References
IFN
family
T cells; NK cells Activates monocytes and endothelial
cells;
increases class
I and II MHC molecules
Virus elimination via enhancing monocyte–
macrophages, NK, and CD8
+
T cells; inhibits
HBV replication; contributes to HBeAg
seroconversion
[6–10]
TNF
family
T cells;
macrophages
Acutely infected phase;
inflammation; fever
Liver inflammation and hepatocytes injury; mediates
viral hepatitis complications
[11–13]
IL-2 T cells; NK
cells
T, B cells growth and monocytes
activation
HBV clearance via enhancing CTL and NK cells;
promotes Treg function and causes serious side
effects by administrating high doses
[4,14,15]
IL-12 B cells;
macrophages;
NK; dendritic
cells
Differentiation of naive T cells into a
Th1 cells
Eliminates HBV via promoting and restoring CTL,
NK cells; alleviates liver damage; prompts
regeneration of hepatocytes; promotes HBeAg
seroconversion during acute HBV infection
[16–20]
IL-18 Macrophages;
Kupffer cells;
NK; T cells
CTL and NK cells activation;
balance regulation
of Th1/Th2 cells; promotes
cytokines secretion
On one hand, IL-18 associating with hepatic
deterioration; on the other hand, IL-18 improves
liver damage via inducing Th1 cells and enhancing
CTL
[21–23]
IL-4 T cells Differentiation of naive T cells into
Th2 cells;
regulation of humoral immunity;
macrophages
activation
Suppresses Th1-type response, maintains persistent
HBV replication and promotes immune tolerance;
paradoxically, IL-4 mediates antiviral response via
enhancing NK and T cells secreting IFN and IL-12
[24–26]
IL-6 T cells;
macrophages
B cells growth and differentiation;
promoting acute
phase protein synthesis for acute
phase reactant;
inflammation
Induction of cirrhosis and HCC; eliminating HBV via
inducing humoral and cellular immune response;
resistant to lamivudine during CHB
[27–30]
TGF-βMacrophages; T
cells
Induction of Treg cells and increase
Th17 cells
Inhibits HBVreplication by reducing certain transcription factor, while
contributing to HBV persistence by reducing NK functions and
mediates complications
[31–34]
IL-10 T cells (Th2) Inhibition of proinflammation
cytokines; regulation
of humoral immunity; termination
of
inflammation
Sustains HBV replication and initiates chronic HBV
infection; directs fibrogenesis via inhibition of
IFN-γsecretion
[35–37]
IL-17 T cells (Th17) Mediation of proinflammation
response via inducing IL-6, IL-8,
and TGF-β
Association with hepatitis, cirrhosis and HCC via combination with
proinflammation cytokines; antiviral effects via inhibiting HBV
replication; promotes stellate cells and fibroblast proliferation
[38–42]
IL-23 Dendritic cell;
macrophages
Differentiation of naive T cells into a
Th17 cells;
APCs and CD4
+
T cells activation
Regulation of HBV-mediated hepatitis via IL-23/IL-17 axis [43–45]
IL-22 T cells (Th17,
Th22); NK
and NKT
cells
Against bacterial pathogens in
mucosal immune
system
Prevents liver damage in ConA-induced hepatitis,
while maybe contributing to reverse effects via
recruiting inflammatory cells
[46–51]
IL-21 T cells (Th17);
Tfh cells;
NKT cells
Bcells,CD4
+
T and CD8
+
T cells activation,
proliferation and survival;
induces Th17 cells differentiation;
inflammation and
autoimmune disease
Correlated with end-stage liver disease; age-
dependent response to HBV clearance
[52–56]
42 Clinic Rev Allerg Immunol (2016) 50:41–54
fundamental roles in immune response and are important in
pathophysiological processes, including cellular immunity,
humoral immunity, cell proliferation and differentiation, and
damage repair (Tables 1and 2)[43,64]. With further aware-
ness of the characteristics of Th1, Th2, Th3, and Th17 cells,
understanding the functional features of cytokines secreted by
these lymphocyte subgroups on immune regulation and ef-
fects is important in identifying the pathogenesis of clinical
immune-mediated diseases.
This review describes the current knowledge about how
these cytokines, such as IFN-γ, tumor necrosis factor-alpha
(TNF-α), IL-2, IL-4, TGF-β, IL-10, IL-17, and IL-22, influ-
ence the variable outcome of HBV infection and discusses
their immune signatures associated with clinical recovery and/
or persistent infection.
Th1-Associated Cytokines and HBV Infection
Th1 cells are differentiated from native CD4
+
T cells (Th0
cells) in the presence of IL-12 and IL-18 and mediate cellular
immune responses by producing anti-inflammatory cytokines
such as IFN-γ, IL-2, and TNF-α[6,16,43]. Th1-associated
cytokines are well known for playing a central role in HBV
clearance of both acute and persistent infection and also
contribute to immunopathology and influence the pathogene-
sis of liver disease [6,59].
Interferon
IFN has a pivotal role in the resolution of an acute hepatitis B
episode and may be the main mediator in noncytolytic control
of HBV infection [7]. Increased expression of major histo-
compatibility complex (MHC) molecules on the cell surface is
the main antiviral mechanism of IFN, contributing to antigen
presentation to CD8
+
T cells and leading to dissolution of
target cells. Meanwhile, it can enhance phagocytosis in NK
cells and monocyte–macrophages to target cells infected with
the virus, as well as inhibiting viral replication in newly
infected cells, which is conducive to virus elimination [7,8].
Virus replication often results in rapid induction of IFN by
the infected cell [65]. A robust activation of IFN-γproduction
by innate and adaptive immune cells (e.g., NK and NKT cells,
HBcAg specific CD4
+
and CD8
+
Tcells)in self-resolving
acute HBV infection is characterized with significant inhibi-
tion of HBV replication [6,8]. Several HBV-related studies
have characterized that IFNs can inhibit the HBV replication
cycle both transcriptionally and post-transcriptionally [9]and
are capable of preventing the formation of new HBV capsids,
leading to the destabilization of existing capsids [10,66,67].
Tabl e 2 Clinical characteristics and cytokine responses in the different stages of HBV infection
Stages of HBV
infection
Immune responses
mediated by
cytokines
Clinical manifestation References
Markers of
the virus
Serum
biochemical
parameters,
e.g., ALT
Liver
histopathology
Treatment
Occult HBV infection IL-10↑,TGF-β↑,
IL-17↑, IL-21↑
HBsAg (−)
HBeAg (−)
Anti-HBe (+/−)
HBV-DNA (+)
Normalization No liver
damage
No
therapy
[1,4,60–62]
Inactive carrier IL-10↑, TGF-β↑HBsAg (+)
HBeAg (−)
Anti-HBe (+/−)
HBV-DNA
(<2000 IU/ml)
Normalization Low-grade
inflammation
No
therapy
[1,4,60,61]
Acute self-limit
HBV infection
IL-12↑,IL-18↑, IFN-α↑,
IL-21↑
IFN-γ↑,IL-22↑
IL-6↑, TNF-α↑
IL-10↓,
HBsAg (+)
HBeAg (+)
Anti-HBe (+/−)
HBV-DNA (+)
↑Minimal or
temple Liver
damage
No
therapy
[4,5,51,60]
Active chronic
HBV infection
IL-12↑↑, IL-18↑↑,IFN-α↑,
IL-10↓, IL-17↑, IL-6↑
HBsAg (+)
HBeAg (+/−)
Anti-HBe (+/−)
HBV-DNA (+)
↑↑ Increased liver
damage
Antiviral
therapy
[4,20,60,61,63]
HBV hepatitis B virus, IL interleukin, TGF-βtumor growth factor-beta, IFN-αinterferon-alpha, HBsAg hepatitis B surface antigen, HBeAg hepatitis B e
antigen, Anti-HBe antibody to HBeAg, ALT alanine aminotransferase, (−) negtive, (+) positive, (+/−) positive or negative, ↓decline, ↑elevation, ↑↑
significant elevation
Clinic Rev Allerg Immunol (2016) 50:41–54 43
However, the lack of large IFN-γand TNF-αproduction
by weaker virus-specific T cells has been observed in chronic
HBV patients, who may fail to develop an efficient antiviral-
specific immune response, contributing to virus persistence
and chronic liver immunopathology [8,58]. Induction of
serum IFN-γlevels on treatment in chronic hepatitis B
(CHB) patients can lead to virological control and HBeAg
seroconversion [68].
Tumor Necrosis Factor-Alpha
TNF-αis considered to be a key cytokine involved in the
immune pathogenesis of HBV infection [11]. TNF-αnot only
participates in the host’s anti-HBV immune response but also
mediates liver inflammation and hepatocytes’injury after
HBV infection. For instance, HBV infection leads to elevated
levels of TNF-α, which is relevant to cirrhosis and hepatic
encephalopathy (HE) [12,13].
Studies have shown that serum levels of TNF-αand its
receptor are significantly increased in HBV-infected patients
[57,69]. Genetic analysis revealed an association between the
polymorphism in the promoter region of TNF-αlocated at
−308G/A and HBV disease progression [70,71], while an-
other study proposed that TNF-αpromoter polymorphisms (at
positions −238A, −308A, −857T, −863A, and −1031C) are
important host genetic factors that may determine the clinical
outcome of HBV infection [72]. These data may indicate the
role of TNF-αin the pathogenesis of hepatitis B as well as its
complications.
Interleukin-2
IL-2, also known as T-cell growth factor, is primarily activated
by T cells and partly produced by NK cells and transformed B
cells, which exerts biological effects through combination to
cell surface receptor IL-2R. IL-2 can promote proliferation
and differentiation of T cells and B cells, activate monocytes/
macrophages, and enhance the killing activity of cytotoxic T
lymphocytes (CTL) and NK cells and thus is a vital factor in
the regulation of the immune response [72].
IL-2 production by HBV-specific CD4
+
T cells plays a
major role in the efficient development of effector cytotoxic
CD8
+
T cells and contributes to HBV clearance in human
HBV infection by preventing the virus from stimulating T
cells, B cells, and macrophages to express IL-2R simulta-
neously. T cells with an expression of IL-2R are direct effector
cells that cause liver damage. Meanwhile, the decline of IL-2
weakens the antiviral ability of host and promotes viral repli-
cation, both of which form a vicious circle [14].
Recent results indicate that IL-2 is a potential activator of
memory and effector T cells and can also restore effects and
functions of tolerated T cells to antigens. Thus, many re-
searchers have aimed to focus on whether IL-2 can be applied
in the treatment of hepatitis B. However, high doses of sys-
temic administration of IL-2 not only cause serious side ef-
fects but also promote the function of Treg cells and increase
the activation threshold of antigen-specific T cells [15,73].
Therefore, whether IL-2 can become a therapy target needs
further investigation.
Interleukin-12
IL-12 is a type of multifunctional cytokine mainly secreted by
B cells, monocytes/macrophages, and dendritic cells, which
induce immune responses against viral infections, especially
for HBV. IL-12 can induce Th0 cells to differentiate into Th1
cells, which produce type I cytokines (such as IL-2 and
IFN-γ) and inhibit Th2 cells so that IL-4 and IL-6 cannot be
synthesized. In addition, IL-12 can also cooperate with IL-2 to
promote proliferation and differentiation of cells including
CTL and NK, and help CTL cells, which help eliminate
virus-infected hepatocytes [16].
Studies indicate that, in patients with persistent HBV in-
fection, a decrease in IL-12 can prompt the balance of Th1/
Th2 to tilt forward Th2 and cause noncytotoxic T lymphocyte
response against virus clearance, resulting in chronic HBV
infection [17]. IL-12 can restore consumption of CD8
+
Tcells
and substantially reduce HBV-specific CD8
+
T cells exhaus-
tion. Additionally, it was able to compete against TNF, alle-
viate liver damage from the virus, prompt regeneration of
hepatocytes, improve phagocytosis of Kupffer cells, and pre-
vent further endotoxin damage to liver cells [18,74].
Clinical studies also revealed that IL-12 plays important
roles in HBV infection; patients with long-term forms of
hepatitis B are unable to produce a sufficient amount of this
cytokine [19]. In acute HBV infection, a high concentration of
IL-12 usually occurs, which may be one of the factors that
promote spontaneous negative conversion of HBeAg. During
the process of antiviral therapy, a low serum level of IL-12
suggests the body’s undesirable reaction to antiviral drugs [20,
35]. Decline of IL-12 in chronic hepatitis B patients may be
closely related to maturation and dysfunction of mDC [17].
Interleukin-18
IL-18 is a type of newly discovered multifunctional cytokine,
whichismainlysecretedbyactivatedmonocyte–macro-
phages, Kupffer cells, NK cells, T cells, etc., affecting the
balance regulation of immune responses. IL-18 can initiate a
nonspecific immune response through NK cells, participate in
the balance regulation of Th1/Th2 cells, increase specific
immune response of cytotoxic T lymphocytes (CTL), as well
as enhance other cytokines secretion, which is significant in
immune regulation after pathogen infection [21].
After HBV infection, NK cells are nonspecifically stimu-
lated by IL-18 to secrete IFN-γ, followed by the production of
44 Clinic Rev Allerg Immunol (2016) 50:41–54
IFN-αand IFN-β; these cytokines can further lead to hepato-
cyte dysfunction while inhibiting viral replication. Studies
indicate that the IL-18 level increases with the concentration
enrichment of HBV DNA. On the one hand, with the syner-
gistic effect of IL-12, IL-18 can induce Th1 cells to produce
large amounts of IFN-γ, thus exerting antiviral function;
however, in an immune microenvironment with insufficient
IL-12, IL-18 can only activate Th2 immune response; thus,
the ability of viral abolition declines, and it finally turns to
chronic infection [22]. On the other hand, the abundant IFN-γ
induced by IL-18 can stimulate CD8
+
T cells to express Fas
and upregulate the expression of soluble intercellular adhesion
molecules (SICAM-1) in liver cells, enhancing the cytotoxic-
ity of CTL. Meanwhile, SICAM-1 mediates effector cells to
attack hepatocytes and thereby aggravating hepatocytes’dam-
age in the inflammatory sites of the HBV infection [23,75].
Altogether, IL-18 is a double-edged sword in the pathogenesis
of viral hepatitis; high expression of IL-18 is in favor of virus
clearance but can also lead to sustained chronic liver inflam-
mation. To clarify the role of IL-18 in the pathogenesis of
hepatitis B and hepatocyte injury will provide a new approach
for the prevention and treatment of this refractory disease.
Th2-Associated Cytokines and HBV Infection
Th2 cells are related to proliferation and differentiation of B
cells, as well as antibody generation. Th2 cells mediate the
humoral immune response mainly by secreting cytokines such
as IL-4, IL-6, etc. Th1 type cellular response can be restrained
by Th2 cells and cause a reduced antiviral ability in the host. A
disorder of Th1/Th2 balance is closely associated with the
outcome of HBV infection: When Th1 type response domi-
nates, the body presents self-limited or acute fulminant hepa-
titis; however, when the response of Th2 type dominates, the
body is more likely to turn to chronic hepatitis. Therefore, a
disorder of Th1/Th2 balance is the main factor that causes
chronic HBV infection [76,77].
Interleukin-4
IL-4, mainly secreted by activated Th2 cells, holds the bio-
logical effects of stimulating proliferation and differentiation
of B cells to produce antibodies, promoting CD4
+
Tcellsto
differentiate into Th2 cells, and improving activity of macro-
phages, which is of great significance in the regulation of
humoral and adaptive immunity [24].
An elevated IL-4 level in the peripheral blood of HBV-
infected patients can suppress the production of IFN-γand
Th1-type immune response, resulting in persistent HBV rep-
lication and promotes the formation of immunetolerance [25].
Paradoxically, it was previously reported that IL-4 can
promote T cells and NK cells to secrete IFN-γindirectly by
stimulating dendritic cells (DC) to produce IL-12 without
depending on IL-12; in addition, IL-4 might suppress the
production of HBsAg, as well as the replication of HBV and
thus mediate the host’s antiviral response [24,26]. Building on
the previous sections, it can be seen that IL-4 has dual roles in
the prolonged forms of hepatitis B and further disease
progression.
Interleukin-6
IL-6 is a key cytokine in the body’s immune regulatory
network and is secreted from cells existing in each system of
the human body. The primary biological effects consist of
regulating growth and differentiation of B cells, promoting
synthesis of acute phase protein from hepatocytes, and en-
hancing the killing effect of CTL and NK cells, leading to liver
inflammation and immune damage [27].
IL-6 plays dual roles in the pathogenesis of hepatitis B;
importantly, it can protect the liver from virus infections by
stimulating immune responses against hepatocytes. However,
IL-6 also has an important role in the induction of hepatitis,
cirrhosis, and hepatocellular carcinoma (HCC) [27]. Numer-
ous studies have illustrated that serum IL-6 expression was
significantly higher in CHB patients than that in naturally
immune subjects, which plays key roles in the elimination of
HBV with the induction of humoral and cellular immune
responses [28,29,78]. In parallel with the mentioned study,
another investigation reported that HBV infection leads to
elevated levels of IL-6 in CHB patients who were resistant
to lamivudine in comparison with patients maintaining a
normal response [30]. In addition, it has been established that
this cytokine may participate in pathological complications of
hepatitis B [79]. Based on the presented studies, it appears that
IL-6 is a favorable candidate to induce immune responses
against HBV.
Treg-Associated Cytokines and HBV Infection
Treg cells is a major T cell subset with immunosuppressive
function, which mainly produce immunosuppressive cyto-
kines such as TGF-β, IL-10, and IL-35 and inhibit the activa-
tion of Th1 or Th2 cells, downregulate the immune response,
and induce host immune tolerance, resulting in long-term
persistence of the virus [1,80]. A high viral load has been
shown to suppress CD4
+
and CD8
+
T cells in addition to the
induction of Treg cells in patients with chronic HBV infection
[81,82]. The level of peripheral Treg cells is significantly
increased in patients with chronic hepatitis B. TGF-β,IL-10,
and IL-35 secreted by Treg cells are strongly linked to liver
Clinic Rev Allerg Immunol (2016) 50:41–54 45
cirrhosis and primary hepatocellular carcinoma caused by
chronic hepatitis B [31,81,83].
Tumor Growth Factor-Beta
TGF-βis a 25-kDa cytokine withthree homodimeric isoforms
in humans, including TGF-β1, TGF-β2, and TGF-β3[84].
The TGF-β1 isoform is the most widely expressed isoform of
the family and is referred to as TGF-βin many studies. A
previous investigation demonstrated that TGF-βplays a dual
role in the regulation of immune system and in the responses
against viral infections. TGF-βnot only induces immune
tolerance against HBVantigens via stimulating the differenti-
ation of Treg cells, but also, it has an important role in the
development of cirrhosis of the liver and HCC via increasing
Th17 cells [31,38,85].
Recent findings also indicate that TGF-βcan be considered
as either good or bad for hepatitis B. For example, Hong et al.
reported that TGF-βcan inhibit HBV replication by reducing
hepatocyte nuclear factor-4alpha expression, which is an im-
portant transcription factor required for HBV suppression
[32]. Supporting the role of inhibiting HBV, another investi-
gation suggested that TGF-βcan directly alter hepatocyte
function by regulating micro-RNA expression in hepatocytes
and downregulates NKG2D/DAP10 and 2B4/SAP expression
in NK cells, thus contributing to HBV persistence [33,34,86].
Therefore, the elevated levels of TGF-βcanberegardedasa
crucial step in the mechanism by which HBVescapes the host
immune system. Future studies are needed to improve the
knowledge of the putative roles and detailed mechanisms that
are affected by TGF-βin the pathogenesis of HBV-mediated
hepatitis B and its complications.
Interleukin-10
IL-10, a unique cytokine that was originally discovered in the
murine secretion of Th2 cells, attracts wide concerns from
domestic and foreign scholars because of its inhibition in the
synthesis of Th1 cytokines [87]. IL-10 owns the main biolog-
ical effects of inhibiting the production and release of proin-
flammatory cytokines, thus limiting and terminating inflam-
mation, and promoting the proliferation and differentiation of
B cells to produce antibodies [36].
Previous studies demonstrate that increased expression of
IL-10 is the primary factor that causes chronic HBV infection
[37]. IL-10 can restrain the host’s anti-HBVactivity, leading to
sustained replication and expression of HBV in vivo. An
elevated level of IL-10 is relevant to HBV serum titers and
degree of liver inflammation and also directs the processes of
fibrogenesis and further disease progression [35,37]. Howev-
er, IL-10 is able to induce the activation and proliferation of B
cells and NK cells and enhance the cytotoxicity of CD8
+
T
cells, while inhibiting the production of IFN-γselectively
without changing the cytotoxicity of NK cells. Results obtain-
ed by in vivo and in vitro studies have identified that blockage
of the IL-10 receptors could recover HBV specific CD8
+
T-
cell response, accelerate virus elimination, and suppress the
chronicity of viral infection [37,88]. Therefore, studies of the
effects of IL-10 on HBV infection need to be evaluated by
more investigations.
Th17-Associated Cytokines and HBV Infection
Th17 cells are a newly identified subset of T helper cells and
are closely related to the progression of HBV disease [39].
Research interest in these cells has indicated that patients with
chronic HBV infection were found to have significantly ele-
vated Th17 cell frequency and Th17-secreted cytokines, in-
cluding IL-17A, IL-21, and IL-22, and it was proposed that
these proinflammatory effectors may perform a vital function
in pathogenesis of prolonged hepatitis B infection.
Interleukin-17
IL-17 is considered to be the principal mediator of Th17 cell
functions. The cytokines of the IL-17 family have been re-
ported to be involved in the initiation and maintenance of
immune processes, most notably in inducing and mediating
proinflammatory responses. It has been established that IL-17
binding to the IL-17 receptor on target cells can induce the
expression and secretion of proinflammatory factors, such as
IL-6 and IL-8, which in turn promotes the inflammatory
response [40,41].
Previous studies identified that IL-17 is upregulated in
chronic HBV-mediated inflammation and could be relevant
to the development of liver cirrhosis and HCC [38,39,42]. IL-
17 exerts its antiviral effects by inducing the expression of
MxA and OAS both from messenger RNA (mRNA) levels
and protein levels, which directly inhibits HBV replication
[89]. In addition, IL-17 can also significantly stimulate mono-
cytes and DCs to express IL-17R and produce proinflamma-
tory cytokines, such as IL-1β,TNF-α, IL-6, etc., which are
important for liver damage during hepatitis B progression
[63]. Studies revealed that IL-17 directly mediated the inflam-
matory response in liver cells, and activation of the inflam-
matory response in liver tissue between the liver stromal cells
abundantly expressed TGF-β1, resulting in the conversion to
liver fibrosis in chronic hepatitis B [39].
Supporting the role of prompting stellate cell and fibroblast
proliferation, another investigation suggested that hepatic stel-
late cells also can express IL-17R, and IL-17 can directly
affect IL-17R-expressing cells and exacerbate the inflamma-
tory microenvironment of the liver [63]. Building on the
previous sections, it can be seen that IL-17 may play a critical
46 Clinic Rev Allerg Immunol (2016) 50:41–54
role and exhibits a potential to exacerbate liver damage during
chronic HBV infection. Hence, the phenomenon that IL-17
preferentially increased in HBV infected patients may support
a role for IL-17 in the immunopathogenesis of chronic HBV-
mediated inflammation, but the exact mechanism of action
needs to be investigated further.
Interleukin-23
IL-23 is a recently discovered heterodimeric cytokine of an
IL-12 shared p40 subunit and a unique p19 subunit [90]. It has
been shown that IL-23 regulates a myriad of processes in the
innate and adaptive immune response, including promoting
CD4
+
T-cell proliferation and IFN-γand IL-12 production,
enhancing the antigen presentation abilities of antigen pre-
senting cells (APCs) [44]. IL-23 was also shown to efficiently
stimulate the differentiation of naive CD4
+
TcellsintoTh17
cells in the presence of HBsAg or HBcAg and is an important
mediator of the proinflammatory effects exerted by Th17 cells
in many diseases [43,45].
More recently, it has been reported that HBV-infected
patients have a positive association between IL-23 cytokine
level and Th 17 cell axis and, hence, might play an important
role in the pathogenesis of hepatitis B [43,45]. A study by
Wang et al. [45] indicated that HBsAg and HBcAg can induce
mDCs and macrophages to secrete large amounts of IL-23
protein in a dose-dependent manner in vitro. The IL-23/IL-
23R pathway was strongly activated in liver tissues from
HBV-infected patients. Moreover, IL-23 derived from mDCs
and macrophages can stimulate the capacity to produce IL-17
from CD4
+
T cells in the presence of HBV antigen [43]. These
data provide novel insights into the mechanism of HBV-
induced hepatitis through the IL-23/IL-17 axis.
Interleukin-22
IL-22 is an IL-10 cytokine family member, and the main
sources of IL-22 are Th17 [46], Th22 [47], as well as activated
NK and NKT cells [48]. IL-22 exerts its functions via binding
to a receptor complex composed of IL-10Rβand IL-22R
chains. The latter is highly expressed within the pancreas,
liver, kidney, small intestine, and colon [91,92]. Research
concerning the role of IL-22 remains controversial.
At present, most studies support a protective role for IL-22
in preventing liver damage. In T-cell-dependent hepatitis such
as concanavalin A (ConA)-induced liver injury, IL-22 mRNA
and protein expressions were both significantly elevated in
mice injected with ConA, but they were increased less exten-
sively in the carbon tetrachloride (CCl4)-induced liver injury
model [49,93]. Furthermore, overexpression of IL-22 in the
liver defends against liver injury. Moreover, another study
demonstrated that IL-22-deficient mice are highly sensitive
to ConA-mediated hepatitis and adoptive transfer of IL-22-
expressing Th17 cells into these mice protects against
hepatitis-induced liver injury [94]. Together with the evidence
that liver-specific IL-22 transgenic mice are resistant to hep-
atitis induced by ConA [50], the above studies support a
protective role of IL-22 in liver damage.
However, there are studies demonstrating the pathogenic
activity of IL-22. One group used a transgenic mouse model
of HBV replication and revealed that IL-22 neutralization
improved hepatic expression of proinflammatory genes,
resulting in much more severe liver damage [51]. Further-
more, IL-22 abolition in this transgenic mouse significantly
inhibited the recruitment of antigen-nonspecific inflammatory
cells into the liver. Collectively, these studies suggest that IL-
22 may contribute to the pathogenesis of liver disease by
promoting the migration of inflammatory cells into the liver,
and then plays a proinflammatory role in T-cell induced he-
patocytes [95]. In human studies, it was shown that the level of
serum IL-22 markedly increased in patients with acute hepa-
titis B (AHB), e.g., the IL-22 derived from CD4
+
Tcells [51].
Xiang et al. proposed that IL-22 was highly expressed in the
liver tissue of CHB patients [50,96], suggesting a protective
role in liver inflammation during CHB infection. However,
Park et al. [50] also reported upregulation in patients with
chronic HBV, but in his study, IL-22 levels were positively
correlated with liver inflammatory degree in CHB patients and
accelerated liver cancer promotion in these patients. To date,
there is no general consensus on whether IL-22 is involved in
the progression of HBV as a proinflammatory factor or as a
protective factor. It is possible that IL-22 could exert dual
functions; thus, future clinical investigations to explore the
exact role and design new therapeutic strategy against chronic
HBV infection of IL-22 are worth investigating.
Interleukin-21
Interleukin-21 (IL-21) is a pleiotropic cytokine, which is a
member of the type I cytokine family [97] and is produced by
Th17 cells, Tfh cells, and natural killer T (NKT) cells. The IL-
21 receptor is widely expressed on a variety of immune cells,
including CD8
+
T cells, B cells, NK cells, dendritic cells,
macrophages, and keratinocytes [98,99], and IL-21 signals
via IL-21R as well as the common cytokine receptor γ-chain.
Based on previous studies, IL-21 can affect CD4
+
T cells and
B cells through regulating their activation, proliferation, and
survival [52]. In addition, IL-21 can synergistically promote
the expansion of CD8
+
T cells and induce Th17 differentiation
[53,54] and, hence, is associated with many inflammatory and
autoimmune diseases [100].
Recently, several groups have explored the function of IL-
21 in HBV clearance and its contributions to the severity of
chronic hepatitis B (CHB). One group constructed an animal
model of human HBVand described a phenomenon that adult
mice have higher HBV-specific liver IL-21 production than
Clinic Rev Allerg Immunol (2016) 50:41–54 47
young mice; the low level of IL-21 in younger mice leads to
lower frequencies of virus-specific CD8
+
T- and B-cell re-
sponses. Therefore, it was concluded that IL-21 plays a key
role in the age-dependent response to HBV clearance [55],
which is consistent with another group [56]. Moreover, they
also detected the levels of IL-21 transcripts in humans blood
samples from acutely infected adult patients who had previ-
ously cleared the virus; these patients were found to express
high levels of IL-21, in contrast to low levels expressed in
chronic hepatitis B patients or chronic HBV carriers [55].
With the above results, IL-21 is proved to have a pivotal role
in determining the age-dependent effectiveness of immune
responses. Another group showed that serum IL-21 levels
were higher in ACLF patients and severe CHB patients than
in moderate CHB patients and normal controls, which corre-
lated with end-stage liver disease (MELD) score, survival, and
recovery [101]. Thus, this study suggested IL-21 had a causal
role in the development of severe liver inflammation and was
associated with severity of liver disease.
Experimentally Therapeutic Applications of Cytokines
and Their Receptors
Currently, antiviral drugs, such as lamivudine, adefovir,
entecavir, tenofovir, telbivudine, and interferon (e.g.,
pegylated IFN-α2b), are the commonly used treatment of
chronic HBV infection as summarized in Table 3[3,60,
110]. Although anti-HBV nucleoside drugs mainly target the
viral polymerase activity and exhibit the early virological
response, the long-term effects of most antiviral drugs is still
unsatisfactory (having, e.g., the emergence of HBV mutants
and post-treatment relapse) [60,111]. Emerging evidence has
suggested that restoring the functions of HBV specific CTLs
is the key for effective antiviral therapy [112]. Thus, more
concerns and efforts have been drawn on immunotherapy as
novel therapeutic strategies for HBV [110].
Cytokines, important immunomodulators, serve central
roles in the initiation and regulation of immune responses
and, furthermore, might affect susceptibility to HBV and/or
the outcome of the infection.Much attention has been given to
enhancing T-cell immunity through the use of certain cyto-
kines, which have proven to be essential and necessary for T-
cell survival and function. Therefore, recombinant cytokines
that can be used as therapeutic agents for regulation of the
immune system and in responses against viral infection
followed the development of genetic engineering technology.
IFN-αwas considered the drug of choice for the treatment
of hepatitis B both at home and abroad. It has been reported to
stimulate a predominantly innate immune response, such as
the NK cell response, and increase the cytotoxicity and de-
crease IFN-γproduction of NK cells [113]. Futhermore,
IFN-αexerts their antiviral and virus clearance activities of
the host by inhibiting HBV transcription and replication by
targeting the epigenetic regulation of the covalently closed
circle DNA (cccDNA) viral minichromosome [105], blocking
the formation of an RNA-containing core particle [10]and
expediting the degradation of nucelocapsids that contain
pregenomic HBV RNA [106]. The treatment of IFN-αresults
in a progressive decline of serum HBV DNA, seroconversion
to anti-HBe, and anti-HBs status, as well as ALT normaliza-
tion for both HBeAg-positive and HBeAg-negative CHB
patients [102,107,114]. The combination of IFN-γplus
another Th1-type proinflammatory cytokine TNF-αand se-
quential therapy with cytokine and lamivudine showed a
stronger inhibition of HBV cccDNA compared with
lamivudine alone [115].
However, although with finite duration and absence of
resistance, IFN-αis associated with disadvantages such as
exorbitant cost, the need for subcutaneous injection, contrain-
dication profiles and significant side effects, together with a
relatively small percentage (20–30 %) of HBV-infected pa-
tients who respond to IFN-α-based therapy [116].
Recently, IFN-α-based therapy has been largely replaced by
pegylated interferon-α(PEG IFN-α), where IFN-αis conju-
gated with polyethylene glycol molecules that prolongs its half-
life and facilitates the administration schedule; furthermore,
pegylation has reduced the immunogenicity and antigenicity
for the target protein, resulting in a decreased hypersensitivity
reaction [103]. Pegylated interferon-αenhances recovery of
memory T cells in antigen-positive chronic hepatitis B patients
by downregulating inhibitory receptors (PD-1 and CD244) and
upregulating effector molecules (CD127 and CXCR4) [104].
PEG IFN-α-2a and PEG IFN-α-2b are two forms of PEG
IFN-α, which can be used to treat CHB patients with a similar
efficacy in clinical trials. Currently, the recommended dose and
duration of PEG IFN-α-2a administration for HBeAg-positive
patients is 180 μg/week for 48 weeks [103]. As an authorized
monotherapy drug, PEG IFN-αhas finite duration and a more
durable PEG-IFN-induced HBeAg seroconversion [117]and,
hence, is appropriate for young people who are considering
pregnancy, genotype A patients with high or low levels of HBV
DNA, and genotypes B and C patients with both high levels of
ALT and low levels of HBV DNA [118]. Meanwhile, PEG
IFN-αis endowed with disadvantages, such as inferior tolera-
bility, risk of adverse events, and the need for parenteral ad-
ministration, which is contraindicated in patients with decom-
pensated HBV-related cirrhosis and patients receiving immu-
nosuppressive therapy or chemotherapy [61]. The limited effi-
cacy of IFN-α/PEG IFN-αmonotherapy prompted the treat-
ment optimization, thus providing the opportunity to combine
IFN-αand nucleos(t)ides analogues (NUC) therapy; the com-
bination therapy results indeed showed a slightly better antiviral
effect in HBeAg-positive and in HBeAg-negative patients than
IFN-αmonotherapy [119–122].
48 Clinic Rev Allerg Immunol (2016) 50:41–54
As a new biological agent, TNF-αinhibitors have been
used in the treatment of various autoimmune disease, includ-
ing rheumatoid arthritis (RA), ankylosing spondylitis (AS),
psoriasis, psoriatic arthritis (PsA), and Crohn’sdisease[123,
124], but the safety of TNF-αinhibitors (such as infliximab)
in these patients with HBV infection is still controversial.
TNF-αis an important cytokine involved in host defense,
anti-TNF therapy may allow virus to escape immune control
and increase patients’susceptibility to virus infections. Since
the first case reports of HBV reactivation in patients with anti-
TNF-treatment in 2003 [125], more cases were reported and
concerned on the risk of HBV infection patients treated with
anti-TNF agents [126,127]. HBV reactivation during treat-
ment with TNF-αinhibitors in HBV carriers or chronically
infected HBV patients has been literally referred by several
case reports [128,129]. Concomitant pre-emptive antiviral
therapy could successfully reduce the risk of HBVreactivation
[130]. To the contrary, the safety of TNF blockers in HBV-
infected patients, especially the resolved/occult HBV patients,
has been demonstrated by other case reports [128,131].
However, antivirals are necessary for patients with both auto-
immune disease and HBsAg positive during TNF-αblockers
treatment. In addition, more data were needed for further
evaluations of the safety in HBV-infected patients with anti-
TNF therapy.
As one of the main cytokines involved in inducing cellular
responses against HBV infections, IL-12 [132] is indispens-
able for viral eradication of infected hepatocytes [133]. Al-
though the recombinant human IL-12 (rhIL-12) alone is nei-
ther effective nor without side effects [74], the combined
therapy of lamivudine plus rhIL-12 was able to increase T-
cell reactivity to HBV and the secretion of IFN-γ[108]. A
combination of IL-12 and IL-18 was found to strongly stim-
ulate IFN-γproduction by CD4
+
T cells isolated from the
peripheral blood in response to HBcAg and may contribute to
viral clearance in children with chronic hepatitis B infection
[109]. One study used human recombinant IL-12 directly and
indicated that rhIL-12 downregulates HBV copy numbers in
CHB patients [134]. Another study demonstrated that IL-12
strengthens the response of HBV-specific CD8
+
T cells within
the liver and promotes HBV-specific central memory CD8
+
T
cells and HBeAg seroconversion [18]. Therefore, IL-12 as an
inflammatory cytokine can be considered as a favorable can-
didate for treating HBV infection.
IL-10, an anti-inflammatory Th2 cytokine, is produced by
Th2 lymphocytes, activated macrophages, T regulatory and B
regulatory cells, and inhibits expression of Th1 proinflamma-
tory cytokines such as IFN-γ[135]. It was reported that the
higher level of IL-10 production may restrain the immune
function against HBV in patients with occult HBV infection
[62]. Moreover, inhibition of IL-10 in vitro has been proved to
rescue the polyfunctionality of virus-specific CD8
+
Tcells,
which were regulated via IL-10-producing B cells [37].
TGF-β, also an anti-inflammatory cytokine, is produced
together with IL-10 by Treg cells, which appear to be partially
responsible for liver immune tolerance [136]. In a CHB pa-
tient, inhibition of IL-10 with or without TGF-βwas able to
restore the cytotoxic capacity of liver NK cells to produce
IFN-γ, thereby enhancing their noncytolytic antiviral capacity
[137]. TGF-β1 treatment was able to effectively suppress
Tabl e 3 Effectiveness of antiviral agents for treatment of chronic hepatitis B
Activity Target Action Effect Outcome References
Antiviral: such as
Lamivudine,
Adefovir,
Entecavir,
Telbivudine,
Ten ofo vir,
pegylated IFN-α
HBV Inhibition of formation of
infectious virus;
induction of antiviral
response in cells;
regulation of HBV
cccDNA
Decrease of virus DNA and
correlative antigens (HBsAg,
HBcAg, HBeAg); improved
HBeAg seroconversion;
histological and ALT
improvement and normalization;
restored function of HBV-
specific T cells
Safe and effective in both
HBeAg-positive and negative
chronic hepatitis B; especially,
lamivudine therapy
administrated as
decompensated cirrhosis can
prolong survival and delay or
even make liver
transplantation dispensable;
combination therapy are often
used for mutant HBV strains
[2,3,60,
61,
102–104]
Immune modulatory:
such as IFN-αand
its pegylated
formulations: Peg-
IFN α-2a, Peg-IFN
α-2b, rhIL-12
Host’s
innate
and
acquired
Immunity
Directly activates and
enhances NK cells
effect; increases CTL
and CD4 T cells
response
Reduction of serum HBV DNA;
increased loss of HBeAg and
HBsAg; achieved HBeAg
seroconversion; histological
improvement; normalization of
ALT; increased IFN-γproduction
and IFN-γrelated cytokines and
immune cells against virus
HBV infection effectively under
control by regulating robust
immune response
[18,103,
105–109]
Clinic Rev Allerg Immunol (2016) 50:41–54 49
HBV replication and the levels of viral transcripts, core pro-
tein, and nucleocapsid [32,138]; hence, TGF-β-based immu-
notherapy needs further exploration to achieve an optimal
therapeutic regimen for HBV patients.
Previous data have proposed that injection of granulocyte-
macrophage colony-stimulating factor (GM-CSF), known to
be a good adjuvant for vaccination, before the vaccine might
promote a stronger immune response in humans [139]; recom-
binant human GM-CSF significantly reduced hepatitis B virus
DNA levels [140]. Subsequently, a pilot study demonstrated
that a combined therapy of GM-CSF with a hepatitis B vac-
cine inhibited HBV replication in carrier children [141]. It was
reported that when the HBV-S gene is fused to the GM-CSF
gene, the immune responses induced by HBV-DNA plasmids
both in normal and HBV-transgenic mice can be strengthened,
and HBV-DNA plasmids fused with GM-CSF may be used
for prevention and treatment [142], but meanwhile, it also
showed that GM-CSF was not able to improve the antibody
(Ab) titer or the development of protective immunity by the
HBV vaccination in healthy adult nonresponders [142]. Re-
cently, another study revealed that GM-CSF failed to improve
responses to the booster HBV vaccination in HIV-infected
individuals [143]. Thus, whether GM-CSF is an optimal vac-
cination strategy needs to be evaluated.
Conclusion and Future Prospects
HBV is the most common cause of acute and chronic liver
disease worldwide [144]. Cytokines secreted by immune cells
are crucial in cell mediated and humoral immune responses as
well as in antiviral activity, viral clearance, apoptosis, and
fibrogenesis [109,145]. When affected by HBV, multiple
cytokines and immune cells interact with one another and
form a complex network of immune response, thus prompting
the occurrence and development of hepatitis B (Fig. 1). There
have been several attempts to develop immunotherapy, such
as cytokine therapy, for the control of chronic HBV infection,
and some results are promising. The LCMV mouse model has
showed the essentiality of IL-2 administration timing and
differentiation status in designing IL-2 therapy, indicating a
therapeutic function for IL-2 [146]; TGF-β, which has been
discussed for HBV immunotherapy, is produced by HBV-
specific CD8
+
T cells and contributes to CD8
+
T-cell restora-
tion [147–150]. As a main regulative cytokine of cellular
immunity against viral infection, IL-10 possesses inhibitory
effects on cell-mediated immune responses [151]; thus, its role
in HBV treatment is under exploration. In addition, in a mouse
model of human hepatitis B, IL-21 functions in the therapeutic
augmentation of immune responses to HBV [55]. As another
Th17-secreted cytokine, IL-22 was widely studied regarding
its role in hepatitis. The dual function of IL-22 with both
proinflammatory and protective roles in liver inflammation
and patients with hepatitis B [43] reveals the necessity for
future clinical investigations. Cytokines not only play a key
role in the clearance of HBV [62] but are also indispensable
for NK cells and cytotoxic T cells to balance their function in
immune response [152,153]. Therefore, monitoring the ex-
pression of these cytokines may directly reflect the patholog-
ical condition for liver, which has instructive functions for the
treatment of hepatitis B. Collectively, insight into cytokine
function during the occurrence and development of hepatitis B
is valuable for its prevention and treatment.
Acknowledgments This paper was supported in part by a grant from
the National Natural Science Foundation of China (No. 81171565),
Zhejiang Provincial Natural Science Foundation of China (No.
Fig. 1 Cytokines derived from distinct subsets of CD4
+
T cells affect
anti-HBV ability of host immune response. Upon activation by antigen
presented cells, naive CD4
+
T cells commit to different T cell subsets
including Th1, Th2, Th17, and Tregs under certain stimulation
conditions; afterwards, these subsets of T cells are able to exert separate
functions by producing subset-specific cytokines, thereby playing crucial
roles during the process of anti-viral immunity inHBV infected liver. This
working model have described cytokines secreted by different subsets of
CD4
+
T cells can activate or inhibit the anti-viral ability by enhancing or
attenuating the function of CD8
+
T, CD4
+
T and B cells, which provides
perspicuous thought for further conception and design for HBV-targeted
immunotherapeutics
50 Clinic Rev Allerg Immunol (2016) 50:41–54
LY14H030001), and the Major national S&T Projects for infectious
diseases (2012ZX10002002). We acknowledge Prof. M. Eric Gershwin
and the reviewers for the helpful and thoughtful comments for the
manuscript.
Conflict of Interest Xuefen Li, Xia Liu, Li Tian, and Yu Chen declare
that they have no conflict of interest.
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