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Volume: 15 Issue: 5 October 2017


Association of the Interleukin-27 Gene Expression and Hepatitis B Virus Infection in Liver Transplanted Patients

Objectives: Hepatitis B viral infection is among the most common causes of cirrhosis and hepatocellular carcinoma and a frequent viral indication for liver transplant. Cytokine-mediated immunity plays a critical role in introducing and promoting hepatitis B virus outcomes and in graft microenvironment. Interleukin 27 is a heterodimeric cytokine and a member of interleukin-6/interleukin-12 family. Interleukin-27 shows a broad range of pro- and anti-inflammatory properties and plays a determining role during immune responses in combating hepatitis B virus. Therefore, in this study, the possible association between expressions of interleukin-27 gene with hepatitis B virus infection was evaluated in liver transplant patients.

Materials and Methods: In a cross-sectional study from liver transplant patients with the risk of hepatitis B virus infection who admitted to Namazi Hospital affiliated to Shiraz University of Medical Sciences, 50 patients were selected and subgrouped to 25 hepatitis B virus-infected and 25 noninfected ones between years 2011 and 2013. The 25 healthy controls also were enrolled in this study. The presence of hepatitis B virus infection was assessed using polymerase chain reaction and enzyme-linked immunosorbent assay protocols in liver transplant patients. In addition, the interleukin-27 gene expression level was analyzed using an in-house-SYBER Green real time polymerase chain reaction method. The rate of interleukin-27 gene expression level was statistically analyzed in studied patient groups and controls using the Livak (2-ΔΔCT) method.

Results: The expression level of interleukin-27 gene was increased 10.27- and 2.36-fold in hepatitis B virus-infected and uninfected liver transplanted patients compared with healthy controls.

Conclusion: Hepatitis B virus infection can lead to overexpression of interleukin-27 gene in liver transplant patients compared with uninfected ones and controls. However, further studies are needed to characterize the effective antihepatitis B virus effects of interleukin-27 in liver transplant patients.

Key words : Transplant, IL-27, Hepatitis B virus, Liver transplant


Liver transplant is anticipated as a final cure for patients with end-stage liver diseases. Many diseases and infections can cause severe liver damages that persuade patients receiving liver transplant. Hepatitis B virus (HBV) infection as one of the major global health concerns, produce the most frequent viral indication to liver transplant.1-6 It is estimated that more than 400 million persons worldwide are HBV chronic carriers that can cause around 1 million deaths yearly, and for this reason HBV infection is among the top 10 causes of death.3,7 In the large proportion of HBV-infected individuals do not clear the virus, which may progress to persistent infection with or without liver disease.7 Hepatitis B virus is a noncytopathic virus and the pathogenic mechanisms responsible for assorted outcome are unclear, but the host defense mechanisms may have a role in the outcomes of HBV infection.8,9

Cytokines, which are secretory proteins of immune system, are responsible for starting signaling cascades by binding to their cognate receptors, and are critical in pathogenesis of viruses and interfering in the fate of HBV infection.10,11 According to earlier studies, cytokines—especially inflammatory ones—have determining roles for modulating the intensity and duration of the host immune responses against HBV infection. As a matter of fact, they can inhibit HBV gene expression and replication and play pivotal roles in the clearance of viruses from the rest of infected cells. Commonly, the final result of an viral infection reveals through the dynamic interaction of different cytokine expression profiles during HBV infection.7

Interleukin-27 (IL-27) is a type-I-cytokine belonging to IL-6/IL-12 superfamily of cytokines that consists of IL-12 p40-related protein and IL-12 p35-related polypeptide.7,12-19 The human IL-27 is mainly secreted by antigen-presenting cells like macrophages and dendritic cells, in response to infection caused by intracellular pathogens and host immune stimuli.8,16,20 This cytokine appears to promote development of naive CD4+ T cells into Th1 cells at an earlier stage.7,8,19 For these reasons, it is believe that IL-27 can produce a link between innate and adaptive immunities.7,8 The cellular effects of IL-27 are mediated by binding to its receptor, IL-27R, which includes IL-27 receptor α chain (IL-27Rα, also known as WSX1 or TCCR) and gp130, however, coexpression of both receptor subunits is essential to induce regulatory signal.7,13,14,20,21 Interleukin-27R is expressed by T cells, natural killer cells, B cells, monocytes, mast cells, and neutrophils.22 It is documented that IL-27 has both the pro- and anti-inflammatory properties that promote the early initiation of type 1 helper differentiation as a proinflammatory cytokine and also as an anti-inflammatory cytokine limits the T-cell hyperactivity and production of proinflammatory cytokines.23 It seems that for acting like an immunosuppressor, IL-27 suppresses IL-2 production, inhibits deve­lopment of Th17 cells, and induces IL-10 production.10,24 Certifying these data, one study showed that at the time of HBV infection, IL-27 expression up, regulates both in vivo and in vitro conditions exerted by STAT1 pathway in hepatic stellate cells.20 Besides, the confirmed role of IL-27 in autoimmune diseases, its role in transplant was rarely studied. Le Texier and associates, was only showed the up-regulation of IL-27 in cardiac allograft models.18 Therefore, in this study, expression levels of IL-27 mRNA were evaluated in HBV infected and uninfected liver transplant patients.

Materials and Methods

Patients and samples
In a cross-sectional study, 50 liver transplant patients who underwent surgery at the Transplant ward affiliated to Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran, were enrolled between years 2012 and 2014. These patients divided into 2 equal groups (each 25) of HBV infected (HBV+) and noninfected (HBV-) liver transplant recipients. The 25 healthy persons also were evaluated as normal controls.

Ethylenediaminetetraacetic (EDTA) acid-treated blood samples were collected from each patient groups and controls. Using Ficol, the buffy coat and plasma were isolated from each collected blood sample and preserved in -80°C for further analysis. The study was approved by the Ethical Committee of Shiraz University of Medical Sciences The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. All patients signed written consent.

For a diagnosis of HBV, genomic DNA in studied blood samples, a qualitative PCR technique was used. For determination of the mRNA expression level of IL-27 gene, an in-house-SYBR Green Real-Time PCR was used and glyceraldehyde 3-phosphate dehydro­genase (GAPDH) also considered as internal control. The routine immunosuppressive condi­tioning regimen included tacrolimus or cyclosporine with mycop­henolate mofetil and steroids. Drug dosages were adjusted to maintain target therapeutic blood levels of 200 ng/mL for CsA (5 mg/kg/d) or 10 ng/mL for tacrolimus. Donors were selected on the basis of ABO blood group compatibility. Human leukocyte antigen matching is routinely not done for liver transplant patients in this center. Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) viral infections also were analyzed in all studied patients before transplant operation and patients with negative results were included in this study.

Hepatitis B virus analysis
Enzyme linked immunosorbent assay-based protocol The plasma of EDTA-treated samples of patients and controls were evaluated for presence of HBsAg using third generation ELISA kit (DIAPRO-Italy) according to manufacturer’s instruction.

Polymerase chain reaction-based protocol
Hepatitis B virus genomic DNA was extracted from plasma using DNP Kit (CinnaGen, Tehran, Iran) according to the manufacturer’s instruction. The HBV-DNA was identified in patient samples using specific primers to amplify a fragment of the surface gene using a qualitative HBV PCR detection Kit (CinnaGen) according to the manufacturer’s in­struction.

Cytomegalovirus quantification
Cytomegalovirus (CMV) antigenemia: Active CMV infection was analyzed for all studied patients using the antigenemia method. For this procedure, EDTA-treated whole blood samples were evaluated using the CMV Brite Turbo kit (IQ Products, Groningen, The Netherlands) as previously described.25

Cytomegalovirus real-time polymerase chain reaction
Cytomegalovirus genomic DNA was extracted from plasma samples of transplant patients using Invisorb Spin Virus DNA Mini Kit (Invitek, Birkenfeld, Germany) according to the manufacturer’s instruction. Cytomegalovirus viral load was determined using genesig quantitative real-time PCR kit (Primer Design Ltd TM, Advanced kit, United Kingdom) according to the manufacturer’s instruction.

Polyomavirus BK quantification polymerase chain reaction
Polyomavirus BK genomic DNA was also extracted from patient samples using Invisorb Spin Virus DNA Mini Kit (Invitek, Birkenfeld, Germany) according to the manufacturer’s instruction. The polyomavirus BK DNA load was also quantified in plasma samples of studied patients using a quantitative real-time PCR method using genesig BKV Kit (PrimerDesign Ltd, Southampton, United Kingdom) according to the manufacturer’s instruction.

Ribonucleic acid isolation and cDNA synthesis
Total RNA was extracted by RNX-Plus solution (CinnaGen, Tehran, Iran). The quantity of extracted RNA was evaluated by Nanodrop (measuring the optical density 260/280), and the quality of extracted RNA was assessed by running 3 μL on 1% agarose gel. The quality of RNA was indicated by the lack of a smear on the lower part of the gel (a smear indicates RNA degradation) and by the presence of 28S ribosomal RNA twice as intense as of 18S rRNA. After obtaining good-quality total RNA, cDNA was synthesized using Prime Script RT Reagent Kit (Takara, Japan) according to the manufacturer’s guidelines.

SYBR green real time polymerase chain reaction
For the quantitative analysis of IL-27 mRNA expression profile in the under studied patient groups and controls, SYBR Green Real-Time PCR method was performed. Glyceraldehyde 3-phosphate dehydro­genase gene was used as internal control for minor fluctuations. Polymerase chain reaction program and primer sequences are summarized in Table 1. Melt curve was analyzed to confirm the specificity of reaction at the end of program. To check specificity of amplification reaction, melting-curve analysis was evaluated. The results for the target genes were measured as fluorescent signal intensity and normalized to the internal standard gene GAPDH.

Statistical analyses
The statistical differences in the expression level of IL-27 and the fold changes in patients and controls were compared via analysis of variance (ANOVA) and the Livak (2-ΔΔCT) methods. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 19.0, IBM Corporation, Armonk, NY, USA). P values less than .05 were considered significant.


Patients’ profile
Hepatitis B virus infection was confirmed and rules out in HBV+ and HBV- liver transplant patient groups using HBsAg and PCR protocols. The age range in HBV+ group was between 31 and 74 years old, with mean of 53.24 ± 10.36 years old. This group was also composed of 18 males (72%) and 7 females (28%). The HBV-group consisted of 25 patients with age range between 1 and 59 years old, with mean of 32.78 ± 17.57 years old. The 13 HBV- patients (52%) were male and rest were female (12 of 25; 48%). The age range was between 22 and 55 years old, with mean of 28.6 ± 6.4 years old in healthy controls. The 16 controls (64%) were male and rest were female (9 of 25; 36%). The most frequent ABO blood group was O+ in HBV+ and B+ in HBV-transplanted patients. Details of Demographic and Laboratory Information of liver transplant patient groups and controls are shown in Table 2. The distribution frequency of the underlying diseases in both HBV+ and HBV- liver transplanted patients are shown in Table 3. The highest frequency of the underlying diseases was autoimmune hepatitis and primary sclerosing cholangitis in HBV+ and HBV- patients.

Other viral infections
Active CMV infection and CMV DNAmia and also polyomavirus BK genomic DNA were not found in any HBV+ and HBV- liver transplanted patients.

Interleukin-27 gene expression in hepatitis B virus-infected and uninfected liver transplant patients and controls
The mRNA expression level of IL-27 gene was significantly higher in HBV+ (P = .001) and HBV- (P = .029) patient groups in comparing with controls, separately (Figure 1). Significant higher level of the IL-27 mRNA expression was found in HBV+ com­pared with HBV- liver transplanted patients (P = .005; Figure 1).

Interleukin-27 gene expression fold change in hepatitis B virus-infected and uninfected liver transplant patients
IL-27 gene was significantly higher expression (10.27 times) in the PBMCs of HBV+ liver transplanted patients compared with controls. The expression level of IL-27 gene was increased 2.36 times in HBV-liver transplant patients compared with controls (Figure 2). Finally, IL-27 gene expression level was increased significantly in HBV+ compared with HBV-liver transplanted patients (Figure 2).

Correlation between normalized expressions of IL-27 with risk factors in hepatitis B virus-infected and uninfected liver transplant patients.
The possible association between the expression of IL-27 gene with risk factors; age, sex, blood groups, liver indices and weight in HBV+ and HBV- liver transplanted patients, was checked. These results did not reveal any significant correlation between expressions of IL-27 with studied risk factors (Table 4).


Hepatitis B virus with more than 400 million carriers makes it one of the most terrific viral pathogen worldwide for public health.8,26,27 End-stage HBV-related liver disease may finally lead to need of liver transplant1,6 and recurrence of HBV in immuno­compromised liver transplanted patients can increase the risk of graft failure.28-30 As the liver transplant is a costly and invasive therapy for most of end-stage liver diseases, posttransplant survival of the grafted liver is an important duty and management of HBV in liver recipients has become important.29,31 On the other hand, cytokines as potent immunomodulatory molecules play crucial roles in the inflammatory process, so they could determine the condition of liver microenvironment and might modulate the immune response toward rejection or acceptance of grafted liver.32 Recent studies suggest that Th1 and Th2 cytokines may contribute to successful treatment of HBV and HCV persistent infections.33 Little is known about the role of IL-27 in HBV pathogenesis in liver-transplanted patients, therefore, in this study the possible association of the mRNA expression level of IL-27 gene with HBV infection was evaluated.

Interleukin-27 as a heterodimeric cytokine is composed of 2 subunits; IL-27p28 and EBI3,12 which are secreted from antigen-presenting cells, mac­rophages and dendritic cells at the time of infections, which can progress to naïve CD4+ T cells preliminarily. This cytokine starts its role in the cells by binding to its receptor, which is commonly expressed by different immune cells.8,16,20 Interleukin-27 cytokine as a mediator between the innate and adaptive immune system, has both immune stimulatory and inhibitory effects that is mediated through the activation of STAT1 and STAT3.34 Interleukin-27 is known to be elevated in several human autoimmune diseases naming for example Crohn disease, uveitis, multiple sclerosis, and other Th1-associated granulomatous diseases.21,35 Elevated levels of IL-27 protein and gene expression were detected in rheumatoid arthritis synovial membranes and fluid in human murine models.36

This cytokine is important in host defense against viral infections such as HCV.35 The property of IL-27 which, on one hand, can activate inflammatory immune responses and on the other hand can suppress immune responses is a dilemma in deciding about its role in any related diseases.12 It is believed that proinflammatory properties of IL-27 is due to the fact that IL-27 increase production of IFN-γ by CD4+ T cells, which have IL-27 receptor on their surface, and also starting signals through IL-27 synthesis, activates STAT1 and then T-bet transcription factor, which these phenomenon renders to activation the genes that are capable in Th1 cells polarization and responses again like IFN-γ.37 During the early phase of HBV infection IL-27 promotes Th1 pathway, coordinated innate and adaptive cell-mediated immune responses to clear HBV. In later stage of HBV infection, IL-27 led immune system to generate a mild protective inflammatory response.8 It is mentioned that IL-27 can inhibit function of neutrophil and development of Treg and also initiate Th1 responses, which may contribute to promotion of allograft acceptance and limitation of ischemia-reperfusion injury.38 Limited information has existed on the study of the determinative role of IL-27 function on the viral pathogenesis. However, results of current study showed that IL-27 is expressed at high levels in HBV+ versus HBV- liver transplant patients, suggesting that IL-27 expression may be associate with progression of HBV infection. Also, the mean difference in IL-27 gene expression between healthy subjects and transplanted patients with HBV infection versus uninfected ones is statistically significant.

Research shows that IL-27 is involved in defense against microbial products and autoimmune diseases.16,39-40 Previous studies also emphasized on the role of IL-27 in bacterial infections.41 Jung and associates showed the role of IL-27 and also STAT-3 on lysosomal activity, which finally renders to enhanced trafficking of mycobacteria toward lyso­somes in human macrophages.41 The role of IL-27 in the pathogenesis of other viral infections show its prominent role in removing viruses, for example; study of the role of IL-27 in influenza virus type A replication and gene expression showed inhibition and antiviral function of IL-27 which enforced by activation of STAT1/2/3.42

Wang and associates carried out a gene ex­pression profiling study and found that IL-27 serum levels were significantly higher in HBV-infected patients in comparing with healthy controls.7 Zhu and associates determined the correlation between HBV infection and IL-27 gene expression, using semiquantitative RT-PCR and ELISA method which results showed that IL-27 was significantly elevated in patients as compared to healthy individuals.8 Researchers also showed that IL-27 may play a determinative role in the context of liver infla­mmation by counteracting with different liver cell types.20

Also, one study reported that serum IL-27 levels of the patients with multiple sclerosis decrease significantly than controls which show IL-27 may have a suppressive role on inflammatory process of multiple sclerosis.41 Another research claimed that IL-27 is a novel anti-HIV cytokine that inhibits HIV replication by activating multiple interferon-inducible genes in macrophages.42 Furthermore, Le Texier and associates showed that IL-27 along with TGFβ1 play a role in model of rodent cardiac allograft tolerance that their expression correlates with inhibition of Th17 differentiation and with expansion of regulatory CD4+ CD25+ T cells.18 It also has been proposed that IL-27 can show as effective therapeutic agent suppresses differentiation of Th17 cells in autoimmune diseases like Sjögren syndrome.10,43-46


Based on these findings, HBV infection may overexpress IL-27 gene in liver transplant patients compared with uninfected ones and healthy controls. Thus, concomitant to these results and for existence of little earlier information about the accurate role of IL-27 in HBV pathogenesis in different patients especially liver-transplanted recipients’ further studies in larger population and even with longer follow-up are needed.


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Volume : 15
Issue : 5
Pages : 554 - 560
DOI : 10.6002/ect.2015.0243

PDF VIEW [508] KB.

From the 1Department of Biology, Faculty of Sciences, Zabol University, Zabol; the 2Shiraz Transplant Research Center-Shiraz University of Medical Sciences-Shiraz; the 3Department of Physiopathology, Faculty of Veterinary Medicine, Zabol University, Zabol; and the 4Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Razavi Khorasan, Iran
Acknowledgements: This study was financially supported by Shiraz University of Medical Sciences, and they have no conflicts of interest to declare.
Corresponding author: Ramin Yaghobi, Shiraz Transplant Research Center, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.
Phone / Fax: +98 713 628 1529