Oncostatin M Induces IFITM1 Expression to Inhibit Hepatitis B Virus Replication Via JAK-STAT Signaling

Yuchen Ye; Ya Fu; Caorui Lin; Ye Shen; Qingqing Yu; Xiaobao Yao; Qunfang Huang; Can Liu; Yongbin Zeng; Tianbin Chen; Songhang Wu; Zhen Xun; Qishui Ou

doi:10.1016/j.jcmgh.2023.10.003

Oncostatin M Induces IFITM1 Expression to Inhibit Hepatitis B Virus Replication Via JAK-STAT Signaling

Cell Mol Gastroenterol Hepatol. 2024;17(2):219-235. doi: 10.1016/j.jcmgh.2023.10.003. Epub 2023 Oct 23.

Authors

Yuchen Ye¹, Ya Fu², Caorui Lin², Ye Shen³, Qingqing Yu³, Xiaobao Yao¹, Qunfang Huang¹, Can Liu², Yongbin Zeng², Tianbin Chen¹, Songhang Wu⁴, Zhen Xun⁵, Qishui Ou⁶

Affiliations

¹ Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, China.
² Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Department of Laboratory Medicine, National Reginal Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
³ Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, China.
⁴ Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
⁵ Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Department of Laboratory Medicine, National Reginal Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China. Electronic address: xunzhen@fjmu.edu.cn.
⁶ Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Department of Laboratory Medicine, National Reginal Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China. Electronic address: ouqishui@fjmu.edu.cn.

Abstract

Background & aims: Functional cure is achieved by a limited number of patients with chronic hepatitis B (CHB) after nucleotide analogue(s) and interferon treatment. It is urgent to develop therapies that can help a larger proportion of patients achieve functional cure. The present study was designed to explore the anti-hepatitis B virus (HBV) potency of interleukin-6 family cytokines and to characterize the underlying mechanisms of the cytokine displaying the highest anti-HBV potency.

Methods: HBV-infected cells were used to screened the anti-HBV potency of interleukin-6 family cytokines. The concentration of oncostatin M (OSM) in patients with chronic HBV infection was examined by enzyme-linked immunosorbent assay. The underlying mechanism of OSM anti-HBV was explored through RNA-seq. C57BL/6 mice injected with rAAV8-1.3HBV were used to explore the suppression effect of OSM on HBV in vivo.

Results: OSM is the most effective of the interleukin-6 family cytokines for suppression of HBV replication (percentage of average inhibition: hepatitis B surface antigen, 34.44%; hepatitis B e antigen, 32.52%; HBV DNA, 61.57%). Hepatitis B e antigen-positive CHB patients with high OSM levels had lower hepatitis B surface antigen and hepatitis B e antigen than those with low levels. OSM activated JAK-STAT signaling pathway promoting the formation of STAT1-IRF9 transcription factor complex. Following this, OSM increased the expression of various genes with known functions in innate and adaptive immunity, which was higher expression in patients with CHB in immune clearance phase than in immune tolerance phase (data from GEO: GSE65359). Interferon-induced transmembrane protein 1, one of the most differentially expressed genes, was identified as an HBV restriction factor involved in OSM-mediated anti-HBV effect. In vivo, we also found OSM significantly inhibited HBV replication and induced expression of antiviral effector interferon-induced transmembrane protein 1.

Conclusions: Our study shows that OSM remodels the immune response against HBV and exerts potent anti-HBV activity, supporting its further development as a potential therapy for treating CHB.

Keywords: Hepatitis B Virus; Interferon-Induced Transmembrane Protein 1; Interleukin-6 Family Cytokines; JAK-STAT Signaling; Oncostatin M.

MeSH terms

Animals
Hepatitis B Surface Antigens
Hepatitis B e Antigens
Hepatitis B virus* / genetics
Hepatitis B* / drug therapy
Humans
Interferons
Interleukin-6
Mice
Mice, Inbred C57BL
Oncostatin M / pharmacology
Signal Transduction
Virus Replication

Substances

Hepatitis B Surface Antigens
Oncostatin M
Hepatitis B e Antigens
Interleukin-6
Interferons