Serum IL-33 levels are associated with liver damage in patients with chronic hepatitis C.
ABSTRACT Interleukin-33 (IL-33) is associated with the development of Th2 responses. This study examined the potential role of IL-33 in the pathogenic process of chronic hepatitis C (CHC) in Chinese patients. The levels of serum IL-33 and sST2 in 154 patients with CHC, 24 with spontaneously resolved HCV (SR-HCV) infection and 20 healthy controls (HC), were analyzed by ELISA. The concentrations of serum IL-2, IFN-γ, TNF-α, IL-4, IL-6, and IL-10, HCV loads, ALT, AST, and HCV-Ab were measured. We found that the levels of serum IL-33 in CHC patients were significantly higher than those of SR-HCV and HC but decreased after treatment with interferon for 12 weeks. More importantly, the levels of serum IL-33 were correlated with the concentrations of ALT and AST in CHC patients. The levels of serum sST2, as a decoy receptor of IL-33, were significantly higher in CHC and SR-CHC patients than those in HC, and there was no correlation between the levels of serum sST2 and IL-33. The concentrations of serum IFN-γ and IL-6 in CHC patients were significantly lower than those of SR-HCV. These data suggest that IL-33 may be a pathogenic factor contributing to CHC-related liver injury.
- SourceAvailable from: Jiaren Sun
Dataset: Liang et al J Immunol 2013
- [Show abstract] [Hide abstract]
ABSTRACT: Heroin-dependent patients typically contract hepatitis C virus (HCV) at a disproportionately high level due to needle exchange. The liver is the primary target organ of HCV infection and also the main organ responsible for drug metabolism. Methadone maintenance treatment (MMT) is a major treatment regimen for opioid dependence. HCV infection may affect methadone metabolism but this has rarely been studied. In our current study, we aimed to test the hypothesis that HCV may influence the methadone dosage and its plasma metabolite concentrations in a MMT cohort from Taiwan. A total of 366 MMT patients were recruited. The levels of plasma hepatitis B virus (HBV), HCV, human immunodeficiency virus (HIV) antibodies (Ab), liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were measured along with the urine morphine concentration and amphetamine screening. Of the 352 subjects in our cohort with HCV test records, 95% were found to be positive for plasma anti-HCV antibody. The liver functional parameters of AST (Wilcoxon Rank-Sum test, P = 0.02) and ALT (Wilcoxon Rank-Sum test, P = 0.04), the plasma methadone concentrations (Wilcoxon Rank-Sum test, P = 0.043) and the R-enantiomer of methadone concentrations (Wilcoxon Rank-Sum test, P = 0.032) were significantly higher in the HCV antibody-positive subjects than in the HCV antibody-negative patients, but not the S-EDDP/methadone dose ratio. The HCV levels correlated with the methadone dose ([Formula: see text] = 14.65 and 14.13; P = 0.029 and 0.03) and the S-EDDP/methadone dose ratio ([Formula: see text] = -0.41 and -0.40; P = 0.00084 and 0.002) in both univariate and multivariate regression analyses. We conclude that HCV may influence the methadone dose and plasma S-EDDP/methadone dose ratio in MMT patients in this preliminary study.PLoS ONE 01/2013; 8(7):e69310. · 3.53 Impact Factor
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ABSTRACT: The IL-33/ST2 axis is known to be involved in liver pathologies. Although, the IL-33 levels increased in sera of viral hepatitis patients in human, the cellular sources of IL-33 in viral hepatitis remained obscure. Therefore, we aimed to investigate the expression of IL-33 in murine fulminant hepatitis induced by a Toll like receptor (TLR3) viral mimetic, poly(I:C) or by pathogenic mouse hepatitis virus (L2-MHV3). The administration of poly(I:C) plus D-galactosamine (D-GalN) in mice led to acute liver injury associated with the induction of IL-33 expression in liver sinusoidal endothelial cells (LSEC) and vascular endothelial cells (VEC), while the administration of poly(I:C) alone led to hepatocyte specific IL-33 expression in addition to vascular IL-33 expression. The hepatocyte-specific IL-33 expression was down-regulated in NK-depleted poly(I:C) treated mice suggesting a partial regulation of IL-33 by NK cells. The CD1d KO (NKT deficient) mice showed hepatoprotection against poly(I:C)-induced hepatitis in association with increased number of IL-33 expressing hepatocytes in CD1d KO mice than WT controls. These results suggest that hepatocyte-specific IL-33 expression in poly(I:C) induced liver injury was partially dependent of NK cells and with limited role of NKT cells. In parallel, the L2-MHV3 infection in mice induced fulminant hepatitis associated with up-regulated IL-33 expression as well as pro-inflammatory cytokine microenvironment in liver. The LSEC and VEC expressed inducible expression of IL-33 following L2-MHV3 infection but the hepatocyte-specific IL-33 expression was only evident between 24 to 32h of post infection. In conclusion, the alarmin cytokine IL-33 was over-expressed during fulminant hepatitis in mice with LSEC, VEC and hepatocytes as potential sources of IL-33.PLoS ONE 01/2013; 8(9):e74278. · 3.53 Impact Factor
Hindawi Publishing Corporation
Mediators of Inflammation
Volume 2012, Article ID 819636, 7 pages
SerumIL-33 LevelsAreAssociated withLiverDamage in
Patients withChronicHepatitis C
JunyanFeng,1Junqi Niu,2and YanfangJiang1
1Department of Central Laboratory, The Second Part of First Hospital, Jilin University, Changchun 130032, China
2Department of Hepatology, First Hospital, Jilin University, Changchun 130032, China
Correspondence should be addressed to Junqi Niu, firstname.lastname@example.org and Yanfang Jiang, email@example.com
Received 23 August 2011; Revised 18 October 2011; Accepted 19 October 2011
Academic Editor: Giamila Fantuzzi
Copyright © 2012 Juan Wang et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Interleukin-33 (IL-33) is associated with the development of Th2 responses. This study examined the potential role of IL-33 in
the pathogenic process of chronic hepatitis C (CHC) in Chinese patients. The levels of serum IL-33 and sST2 in 154 patients
with CHC, 24 with spontaneously resolved HCV (SR-HCV) infection and 20 healthy controls (HC), were analyzed by ELISA.
The concentrations of serum IL-2, IFN-γ, TNF-α, IL-4, IL-6, and IL-10, HCV loads, ALT, AST, and HCV-Ab were measured. We
found that the levels of serum IL-33 in CHC patients were significantly higher than those of SR-HCV and HC but decreased after
and AST in CHC patients. The levels of serum sST2, as a decoy receptor of IL-33, were significantly higher in CHC and SR-CHC
patients than those in HC, and there was no correlation between the levels of serum sST2 and IL-33. The concentrations of serum
IFN-γ and IL-6 in CHC patients were significantly lower than those of SR-HCV. These data suggest that IL-33 may be a pathogenic
factor contributing to CHC-related liver injury.
Hepatitis C virus (HCV) is one of the major causes of
chronic liver disease in the world . More importantly,
many of those patients with chronic hepatitis C eventually
develop cirrhosis and hepatocellular carcinoma . Fol-
lowing infection with HCV, only about 15% of patients
can clear the virus, while 60–80% of patients develop
persistent chronic infection [3, 4]. Previous studies have
revealed that the persistence of viral infection and chronic
inflammation are dependent on the interaction among the
virus, hepatocyte, and the host immune system [4, 5]. The
viral infection and related hepatocyte injuries are known to
suppress the immune system [6, 7]. Although experimental
evidence suggests that antigen-specific Th1 immunity and
proinflammatory cytokines play an important role in the
HCV-related liver injury and clearance of viruses [8–10], the
pathogenesis of chronic HCV infection has not been fully
Interleukin-33 (IL-33) is one of the newly described
tissues and vascular endothelial cells . IL-33 binds
to its heterodimer receptors composed of IL-1 receptor-
related protein ST2 and IL-1 receptor accessory protein
(IL-1RaP) and can activate the MyD88 and NF-κB-related
signal pathway [11, 12]. ST2 has transmembrane form of
ST2 (ST2 or ST2L) and soluble form of ST2 (sST2). ST2 is
expressed on Th2 and mast cells and functions as a mediator
of IL-33 bioactivities, while sST2 acts as a decoy receptor
for IL-33. Biologically, IL-33 induces Th2 cell differentiation
and activates mast cells, leading to Th2 cytokine production
and Th2 response as well as pulmonary and mucosal Th2
inflammation . Furthermore, IL-33 can antagonize the
LPS-induced mortality in a model of septic shock ,
and the levels of serum IL-33 were elevated in SLE and
RA patients . Recently, IL-33 has been found to be an
important factor of the pathogenesis of HIV infection and
dengue virus infection [14, 15]. However, little is known on
2Mediators of Inflammation
whether IL-33 could participate in the pathogenic process of
In the current study, we examined the concentrations
of serum IL-33 and sST2 in patients with chronic hepatitis
C (CHC), individuals with spontaneously resolved HCV
infection (SR-HCV), and healthy controls (HC) to evaluate
the potential role of IL-33/ST2 axis in the pathogenic process
of CHC. Furthermore, we determined the concentrations of
serum IL-33 before and after antivirus therapies in patients
with CHC. We found that IL-33 response appeared to be an
the severity of liver injury in CHC patients. We discuss the
implications of our findings.
2.1. Patients. A total of 154 patients with CHC, 24 cases with
of First Hospital. Another 20 gender-, age- and ethnic-
matched HC were recruited, and they had no historical liver
diseases and no evidence of HBV, HCV, and HDV infection.
Individuals with positive anti-HCV antibodies and serum
HCV RNA for at least six months were diagnosed with
CHC . Individuals with SR-HCV were defined as those
subjects who had prior HCV RNA detection (HCV-Ab+) but
lacked HCV RNA detection for 12 weeks after enrollment in
the absence of treatment . Genotyping of HCV showed
that 22 CHC patients had genotype 2a, 45 had genotype
1b, and 14 had unclassified genotype. Individuals with
historical and current hepatitis B, D virus or HIV infection,
autoimmune hepatitis, or metabolic liver disease, who had
received immunosuppressive therapy or antiviral therapy
during the past 12 months before entry, were excluded. All
Their demographic and clinical characteristics are shown in
Fifty patients with CHC were treated subcutaneously
with 500 million units of a short-acting interferon (SINO-
GEN, Jinan, China) every other day for 12 weeks. The con-
centrations of serum IL-33, sST2, HCV-RNA, ALT, and AST
were measured before and after treatment. Individuals with
100-fold reduced serum virus load were defined as drug-
responsive patients; otherwise, individuals were defined as
drug-nonresponsive patients. Written informed consent was
obtained from individual participants, and the study was
approved by the First Hospital Ethical Committee of Jilin
Peripheral blood samples were obtained from individual
subjects, and their sera were prepared and then stored at
−80◦C till needed. The levels of serum IL-33 were measured
at the entry of individual participants, before and after
treatment of patients with CHC, and the concentrations
of serum IFN-γ, TNF-α, IL-2, IL-4, IL-10, and IL-6 in
individual CHC patients were also determined.
2.2. Measurement of IL-33 and sST2 by ELISA. The concen-
trations of serum IL-33 and sST2 in individual patients and
healthy controls were determined by ELISA using human
Table 1: Demographic characteristics and clinical features of par-
15/9 Sex (M/F)
Normal values (NA): ALT ≤ 50IU/L; AST ≤ 40IU/L; HCV RNA ≤
300copies/mL;∗P < 0.05 versus SR-HCV or HC. Data were expressed as
median and range.
IL-33 and sST2 ELISA kits, according to the manufactur-
ers’ instruction (Roche Diagnostics, Lewes, UK). Briefly,
individual sera at 1:4 dilutions were subjected to ELISA
analysis, and the concentrations of serum IL-33 and sST2 in
curve established using the recombinant IL-33 and sST2
provided. The detection limitation of the IL-33 and sST2
ELISA kit was 0–16ng/L and 1.6ng/L, respectively.
2.3. Cytometric Bead Array of Serum Cytokines. The concen-
trations of serum cytokine levels (IFN-γ, TNF-α, IL-2, IL-4,
IL-10, and IL-6) were determined by cytometric bead array
(CBA) , according to the manufacturer’s protocol (BD
25μL of individual sera was used in duplicate for analysis,
as described previously . The concentrations of serum
cytokines were quantified using the CellQuestPro and CBA
software (Becton Dickinson) on a FACSCalibur cytometry
2.4. Serologic Analysis of Hepatitis. The concentrations of
serum antibodies against HCV were detected by ELISA II
(Abbott Laboratories, Abbott Park, USA) . The levels
of serum ALT and AST were detected using a Biochem-
istry Automatic Analyzer (Roche Diagnostics, Branchburg,
USA). The amounts of serum HCV RNA were measured
by quantitative PCR assay using a luciferase quantization
detection kit, following the protocols (Roche Amplicor,
Basel, Switzerland). The detection limit of viral RNA was
2.5. Statistical Analysis. The data are expressed as median
and range unless specified. The differences between the
groups were analyzed by Wilcoxon-rank sum test and chi-
square test using the SPSS 14.0 software. The relationship
between variables was evaluated using the Spearman rank
Mediators of Inflammation3
P = 0.001
P < 0.001
P < 0.001
ALT <50 (IU/L) ALT >50 (IU/L)
P < 0.001
AST <40 (IU/L)
AST >40 (IU/L)
0 200400600800 1000
P < 0.001, r = 0.388
P = 0.001, r = 0.400
0200 400600 8001000
Figure 1: The levels of serum IL-33. The concentrations of serum IL-33 in individual CHC patients, those with SR-HCV and HC, and the
levels of serum ALT and AST were determined by ELISA and automatic enzymatic assays, respectively. The potential association of the levels
of serum IL-33, ALT, and AST was analyzed using the Spearman rank correlation test. Data are expressed as the mean values of individual
participantsfromtwoseparateexperiments.Thehorizontallinesindicatethemedianvalues ofdifferentgroups.(a)Thebasallevels ofserum
IL-33; (b) the levels of serum IL-33 in those with different levels of serum ALT; (c) the levels of serum IL-33 in those with different levels of
serum AST; (d) the correlation between the levels of serum IL-33 and ALT; (e) the correlation between the levels of serum IL-33 and AST.
HC: healthy controls; CHC: patients with CHC; SR-HCV: individual with spontaneously resolved HCV patients (SR-HCV).
correlation test. A two-sided P value <0.05 was considered
To determine the potential role of IL-33 in the pathogenic
process of CHC, a total 154 patients with CHC, 24 with
SR-HCV, and 20 with HC were sequentially recruited. As
expected, there was no significant difference in the distri-
bution of age and gender among these groups of subjects,
but the concentrations of serum ALT and AST in patients
with CHC were significantly higher than those in the HC
and those with SR-HCV (Table 1). While high levels of virus
RNA were detected in CHC patients, there was no detectable
viremia in both HC and SR-HCV. In addition, the anti-HCV
antibody was detected in CHC patients and individuals with
SR-HCV, but not in HC.
Analysis of serum cytokines indicated that there was
no significant difference in the concentrations of serum IL-
33 between individuals with SR-HCV and HC, while the
concentrations of serum IL-33 in patients with CHC were
significantly higher than those in individuals with SR-HCV
and HC (P < 0.001, Figure 1(a)).
Furthermore, stratification of patients with CHC
revealed that the concentrations of serum IL-33 in CHC
patients with abnormal levels of serum ALT (>50units/L)
or AST (>40units/L) were significantly higher than those
in CHC patients with normal levels of ALT (<50units/L) or
AST (<40units/L), respectively (P < 0.001, P < 0.001, resp.,
Figures 1(b) and 1(c)). The concentrations of serum IL-33
in CHC patients were correlated positively with the levels
of serum ALT and AST (r = 0.388, P < 0.001; r = 0.400,
P < 0.001, resp., Figures 1(d) and 1(e)). Apparently, IL-33
is a pathogenic factor, associated with the damage of the
4Mediators of Inflammation
P = 0.004
P = 0.041
Figure 2: The levels of serum sST2. The concentrations of serum
sST2 in individual CHC patients, those with SR-HCV and HC,
were determined by ELISA. Data are expressed as the mean values
of individual participants from two separate experiments. The
horizontal lines indicate the median values of different groups.
liver in CHC patients. Further analysis revealed that the
levels of serum sST2 were significantly higher in CHC and
SR-CHC patients than that in HC (P = 0.004, P = 0.041,
resp., Figure 2), but there was no significant correlation
between the levels of serum IL-33 and sST2 in those subjects
(r = −0.050, P = 0.678). Moreover, the concentrations
of serum IFN-γ and IL-6, but not TNF-α, IL-2, IL-10,
and IL-4, in patients with CHC, were significantly lower
than those in individuals with SR-HCV (Figures 3(a) and
3(b)). Following treatment of CHC patients with IFN for
12 weeks, 45 out of 50 CHC patients displayed dramatically
reduced levels of serum HCV virions. Notably, treatment
with IFN remarkably reduced IL-33 responses in those
patients because the levels of serum IL-33 in patients with
CHC after treatment with IFN were significantly lower than
those before treatment. (P = 0.002, Figure 4(a)). However,
treatment with IFN for 12 weeks did not change significantly
in the levels of serum sST2 in CHC patients (P = 0.641,
IL-33 is a multifunctional cytokine involved in various
disease conditions [21–23]. IL-33, through the receptor
complex composed of ST2 and IL-1RaP, can activate the
MAP kinase and NF-κB signal pathways and promote Th2
response and cytokine production . Indeed, intranasal
administration of IL-33 triggered an immediate allergic
response in the airway, and endogenous IL-33 contributes to
airway inflammation . A recent study revealed that the
levels of serum IL-33 were elevated in SLE and RA patients
and correlated with the levels of serum ESR and CRP, two
inflammation markers, indicating that IL-33 may participate
in the acute-phase response of SLE . In addition, IL-33
can protect against septic shock by enhancing neutrophils
infiltration at the site of inflammation . Other studies
suggest that IL-33 participates in the pathogenic process
of acute hepatitis induced by Con-A [25, 26], and IL-
33 overexpression is associated with the development of
HBV/HCV-related liver fibrosis . To investigate the role
of IL-33 in the pathogenic process of CHC, we determined
the levels of serum IL-33 and sST2 in 154 CHC patients. We
found that the levels of serum IL-33 in CHC patients were
significantly higher than in those with SR-HCV and HC.
Furthermore, the levels of serum IL-33 in CHC patients with
abnormal concentrations of ALT or AST were significantly
higher than in those with normal levels of ALT and AST in
this population. In addition, treatment with IFN to inhibit
the replication of HCV dramatically decreased the levels
of serum IL-33 in CHC patients. More importantly, the
concentrations of serum IL-33 were correlated positively
with the levels of serum ALT and AST in CHC patients.
Given that abnormal levels of ALT and AST are indicative
of abnormal liver function and injuries, our data suggest that
IL-33 may be a pathogenic factor of the pathogenic process
of CHC in Chinese patients. Therefore, if the levels of serum
IL-33 are also correlated with pathogenic degrees of the liver
in CHC patients, the levels of serum IL-33 may be used as a
new biomarker for the diagnosis of liver damages in CHC
patients. Furthermore, we found that the levels of serum
sST2 were significantly higher in CHC and SR-CHC patients
than those in HC, but were not correlated with the levels
of IL-33 in patients. Treatment with IFN for 12 weeks did
not significantly change the levels of serum sST2. A previous
study has shown that the levels of serum sST2 in patients
with acute liver failure are higher than in those with chronic
liver failure and healthy controls . It is possible that high
levels of serum sST2 are an early biomarker of liver injury,
while high levels of serum IL-33 may be associated with the
development and progression of liver fibrosis and damage
. We are interested in further examining the mechanisms
We found that the levels of serum IFN-γ and IL-6 in
supporting the notion that proinflammatory cytokines, such
as IFN-γ and IL-6, are not only important factors for the
clearance of infected HCV, but also for liver injury [29–31].
The lower levels of IFN-γ and IL-6 in CHC patients were
unlikely to have come from the antagonization of IL-33-
induced Th2 responses in those patients, because we failed
to detect significant difference in the levels of serum IL-4
and IL-10 between those CHC patients and SR-HCV and
HC. Given that IL-6 is a critical factor of the functional
development of Th17 cells  and that IFN-γ is an effector
of Th1 response , the lower levels of serum IFN-γ
and IL-6 in those CHC patients indicated continual viral
replication and pathogenic progression. Although IL-33 has
been shown to promote IFN-γ production by invariant NKT
and NK cells , IL-33 may, through an unknown pathway,
Mediators of Inflammation5
P = 0.022
P = 0.033
Figure 3: The basal levels of serum IFN-γ and IL-6. The concentrations of serum IFN-γ and IL-6 in individual participants were determined
by CBA. Data are expressed as the mean values of individual samples from two separate experiments. The horizontal lines show the median.
(a) The levels of serum IFN-γ; (b) the levels of serum IL-6.
P = 0.022
Figure 4: The changes in the levels of serum IL-33 and sST2 in CHC patients with IFN treatment. Data are expressed as the mean values of
individual participants from two separate experiments. The horizontal lines show the median. (a) The changes in the levels of serum IL-33
in CHC patients with IFN treatment; (b) the changes in the levels of serum sST2 in CHC patients with IFN treatment.
downregulate the functional development of HCV-related
Th1 response and inhibit IFN-γ production. However, the
precise mechanisms remain to be further investigated.
In conclusion, our data indicate, for the first time, that
the concentrations of serum IL-33 are significantly higher in
those with SR-HCV and HC and are significantly correlated
with the levels of serum ALT and AST, suggesting that
IL-33 may be a pathogenic factor of HCV-related liver
injury in CHC patients. We recognized that the current
study has limitations, including no source for IL-33 and
no histopathological examination of liver tissues. Although
more detailed studies are necessary to determine the role and
6Mediators of Inflammation
mechanisms of IL-33 in regulating the pathogenic process
of CHC, our novel findings may provide new insights into
understanding the pathogenesis of CHC.
This study was supported by Grants from the National
Natural Science Foundation of China (no. 30972610), Jilin
Province Science and Technology Agency (nos. 200705128
and 20110716), the Chinese Medical Science and Technology
Projects of Jilin Province (no. 08sys-086), the Health Depart-
ment ResearchProjects in Jilin Province (no. 2009Z054), and
the Cutting-edge Science and Interdisciplinary Innovation
Projects of Jilin University. The authors thank Medjaden
Bioscience Limited for assisting in the preparation of this
paper. J. Wang and P. Zhao contributed equally to this study.
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