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Comparison of ISG15, IL28B and USP18 mRNA levels in peripheral blood mononuclear cells of chronic hepatitis B virus infected patients and healthy individuals

Seyed Mohammad Ali Hashemi, Jamal Sarvari, Mohammad Reza Fattahi, Razieh Dowran, Amin Ramezani, Seyed Younes Hoseini




Background: Despite the presence of an efficient vaccine for hepatitis B virus (HBV), it remains a public health challenge, worldwide. The effort to uncovering immune genes attributed to infection outcome is in undergone. The purpose of this study was to evaluate the expression level of Interferon-stimulated Gene 15 (ISG15), Interleukin28B (IL28B) and Ubiquitin specific peptidase 18 (USP18) genes in Peripheral Blood Mononuclear Cells (PBMCs) of patients with chronic active and inactive hepatitis B in comparison with healthy control individuals.

Materials and Methods: This Cross-sectional study was conducted on hepatitis B infected patients that were admitted to Clinic of Liver diseases, Shiraz, between January 2016-2017. Gene expression assay was performed on PBMCs of blood samples by the help of Real-time PCR method. The relative expression of each gene was calculated regarding 2-?Ct formula.

Results: Interleukin 28B gene expression showed no statistically significant difference between three studied groups. The expression level of ISG15 gene was significantly higher in the healthy control group compared to active (P= 0.0068) and inactive chronic subjects(P<0.0001). Similarly, USP18 expression level in the control group was also significantly higher compared to the active (P= 0.0228) and inactive chronic patients (P=0. 0226).

Conclusion: The results of this study showed that the expression level of ISG15 and USP18 but not IL28B were higher in healthy individuals than those infected with HBV. This difference expression may highlight the role of ISG15 and USP18 in immune-related mechanism HBV infection.


Hepatitis B virus, Innate Immunity, ISG15, IL28B, USP18


Ott J, Stevens G, Groeger J, Wiersma S. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012;30(12):2212-9.

Haghshenas MR, Arabi M, Mousavi T. Hepatitis B genotypes in iran. Materia socio-medica. 2014;26(2):129.

Sarvari J, Mojtahedi Z, Taghavi SA, Kuramitsu Y, Shamsi Shahrabadi M, Ghaderi A, et al. Differentially Expressed Proteins in Chronic Active Hepatitis, Cirrhosis, and HCC Related to HCV Infection in Comparison With HBV Infection: A proteomics study. Hepat Mon. 2013;13(7):e8351.

Rehermann B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nature medicine. 2013;19(7):859-68.

Aspinall E, Hawkins G, Fraser A, Hutchinson S, Goldberg D. Hepatitis B prevention, diagnosis, treatment and care: a review. Occupational medicine. 2011;61(8):531-40.


Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol. 2016;16(8):509-23.

Hoan NX, Van Tong H, Giang DP, Toan NL, Meyer CG, Bock C-T, et al. Interferon-stimulated gene 15 in hepatitis B-related liver diseases. Oncotarget. 2016;7(42):67777-87.

Li W, Jiang Y, Jin Q, Shi X, Jin J, Gao Y, et al. Expression and gene polymorphisms of interleukin 28B and hepatitis B virus infection in a Chinese Han population. Liver International. 2011;31(8):1118-26.

Jones DM, Domingues P, Targett-Adams P, McLauchlan J. Comparison of U2OS and Huh-7 cells for identifying host factors that affect hepatitis C virus RNA replication. Journal of General Virology. 2010;91(9):2238-48.

Li Y, Li S, Duan X, Liu B, Yang C, Zeng P, et al. Activation of endogenous type I IFN signaling contributes to persistent HCV infection. Reviews in medical virology. 2014;24(5):332-42.

Smith DB, Mellor J, Jarvis LM, Davidson F, Kolberg J, Urdea M, et al. Variation of the hepatitis C virus 5′ non-coding region: implications for secondary structure, virus detection and typing. Journal of general virology. 1995;76(7):1749-61.

Kim M-J, Yoo J-Y. Inhibition of hepatitis C virus replication by IFN-mediated ISGylation of HCV-NS5A. The Journal of Immunology. 2010;185(7):4311-8.

Kim JH, Luo JK, Zhang DE. The level of hepatitis B virus replication is not affected by protein ISG15 modification but is reduced by inhibition of UBP43 (USP18) expression. Journal of immunology (Baltimore, Md : 1950). 2008;181(9):6467-72.

Qiu X, Hong Y, Yang D, Xia M, Zhu H, Li Q, et al. ISG15 as a novel prognostic biomarker for hepatitis B virus-related hepatocellular carcinoma. International journal of clinical and experimental medicine. 2015;8(10):17140.

Shi X, Chi X, Pan Y, Gao Y, Li W, Yang C, et al. IL28B is associated with outcomes of chronic HBV infection. Yonsei medical journal. 2015;56(3):625-33.

Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. Nature genetics. 2009;41(10):1100-4.

Farrell PJ, Broeze RJ, Lengyel P. Accumulation of an mRNA and protein in interferon-treated Ehrlich ascites tumour cells. 1979.

Sonneveld MJ, Wong VWS, Woltman AM, Wong GL, Cakaloglu Y, Zeuzem S, et al. Polymorphisms near IL28B and serologic response to peginterferon in HBeAg-positive patients with chronic hepatitis B. Gastroenterology. 2012;142(3):513-20. e1.

Liu L-Q, Ilaria R, Kingsley PD, Iwama A, van Etten RA, Palis J, et al. A novel ubiquitin-specific protease, UBP43, cloned from leukemia fusion protein AML1-ETO-expressing mice, functions in hematopoietic cell differentiation. Molecular and cellular biology. 1999;19(4):3029-38.

Li L, Lei Q-s, Zhang S-J, Kong L-n, Qin B. Suppression of USP18 potentiates the anti-HBV activity of interferon alpha in HepG2. 2.15 cells via JAK/STAT signaling. PloS one. 2016;11(5):e0156496.

Feld J, Janssen H, Abbas Z, Elewaut A, Ferenci P, Isakov V, et al. Version 2.0, February 2015. 2015.

Sarvari J, Mojtahedi Z, Kuramitsu Y, Malek‑Hosseini S-A, Shahrabadi MS, Ghaderi A, et al. Differential expression of haptoglobin isoforms in chronic active hepatitis, cirrhosis and HCC related to HBV infection. Oncology letters. 2011;2(5):871.

Rangnekar A, Fontana R. Meta‐analysis: IL‐28B genotype and sustained viral clearance in HCV genotype 1 patients. Alimentary pharmacology & therapeutics. 2012;36(2):104-14.

Peng L, Guo J, Zhang Z, Shi H, Wang J, Wang J. IL28B rs12979860 polymorphism does not influence outcomes of hepatitis B virus infection. Tissue Antigens. 2012;79(4):302-5.

Martin MP, Qi Y, Goedert JJ, Hussain SK, Kirk GD, Hoots WK, et al. IL28B polymorphism does not determine outcomes of hepatitis B virus or HIV infection. Journal of Infectious Diseases. 2010;202(11):1749-53.

Lee I-C, Lin C-H, Huang Y-H, Huo T-I, Su C-W, Hou M-C, et al. IL28B polymorphism correlates with active hepatitis in patients with HBeAg-negative chronic hepatitis B. PLoS One. 2013;8(2):e58071.

Ren S, Lu J, Du X, Huang Y, Ma L, Huo H, et al. Genetic variation in IL28B is associated with the development of hepatitis B-related hepatocellular carcinoma. Cancer immunology, immunotherapy. 2012;61(9):1433-9.

Jeon YJ, Yoo HM, Chung CH. ISG15 and immune diseases. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2010;1802(5):485-96.

Skaug B, Chen ZJ. Emerging role of ISG15 in antiviral immunity. Cell. 2010;143(2):187-90.

Kim KI, Yan M, Malakhova O, Luo J-K, Shen M-F, Zou W, et al. Ube1L and protein ISGylation are not essential for alpha/beta interferon signaling. Molecular and cellular biology. 2006;26(2):472-9.

Broering R, Zhang X, Kottilil S, Trippler M, Jiang M, Lu M, et al. The interferon stimulated gene 15 functions as a proviral factor for the hepatitis C virus and as a regulator of the IFN response. Gut. 2010;59(8):1111-9.

Lebosse F, Testoni B, Fresquet J, Facchetti F, Galmozzi E, Fournier M, et al. Intrahepatic innate immune response pathways are down-regulated in untreated chronic hepatitis B. Journal of hepatology. 2016.

Hoan NX, Van Tong H, Giang DP, Toan NL, Meyer CG, Bock CT, et al. Interferon-stimulated gene 15 in hepatitis B-related liver diseases. Oncotarget. 2016;7(42):67777-87.

Speer SD, Li Z, Buta S, Payelle-Brogard B, Qian L, Vigant F, et al. ISG15 deficiency and increased viral resistance in humans but not mice. Nature communications. 2016;7:11496.

Jiao B, Chen L. The role of USP18 in interferon signaling and inflammation.

Li L, Lei QS, Zhang SJ, Kong LN, Qin B. Suppression of USP18 Potentiates the Anti-HBV Activity of Interferon Alpha in HepG2.2.15 Cells via JAK/STAT Signaling. PLoS One. 2016;11(5):e0156496.

Yang PL, Althage A, Chung J, Chisari FV. Hydrodynamic injection of viral DNA: a mouse model of acute hepatitis B virus infection. Proceedings of the National Academy of Sciences. 2002;99(21):13825-30.

Rehermann B, editor Chronic infections with hepatotropic viruses: mechanisms of impairment of cellular immune responses. Seminars in liver disease; 2007: Published 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Ayoobi F, Hassanshahi G, Zainodini N, Khorramdelazad H, Arababadi MK, Kennedy D. Reduced expression of TRIF in chronic HBV infected Iranian patients. Clinics and research in hepatology and gastroenterology. 2013;37(5):491-5.

Ebrahim M, Mirzaei V, Bidaki R, Shabani Z, Daneshvar H, Karimi-Googheri M, et al. Are RIG-1 and MDA5 Expressions Associated with Chronic HBV Infection? Viral immunology. 2015;28(9):504-8.

DOI: https://doi.org/10.22037/ghfbb.v0i0.1360