IL-35: A Novel Immunomodulator in Hepatitis B Virus-Related Liver Diseases.

Xuefen Li,Weilin Wang,Xia Liu

doi:10.3389/fcell.2021.614847

Abstract

Chronic hepatitis B virus (HBV) infection is a risk factor for liver cirrhosis (LC) and hepatocellular carcinoma (HCC), however, little is known about the mechanisms involved in the progression of HBV-related diseases. It has been well acknowledged that host immune response was closely related to the clinical outcomes of patients with HBV infection. As the factors closely related to the immunomodulatory process, cytokines are crucial in the cell-cell communication and the host responses to HBV infection. Recently, a newly discovered cytokine, designated as interleukin-35 (IL-35), has been proved to be essential for the progression of chronic HBV infection, the development of cirrhosis, the transformation of cirrhosis to HCC, and the metastasis of HCC. Specifically, it showed various biological activities such as inhibiting the HBV-specific cytotoxic T lymphocyte (CTL) proliferation and cytotoxicity, deactivating the immature effector T-cells (Teffs), as well as delaying the proliferation of dendritic cells. It regulated the immune responses by acting as a “brake” on the activation of Teffs, which subsequently played important roles in the pathogenesis of various inflammatory diseases and malignancies. In this review, we focused on the most recent data on the relationship between IL-35 and chronic HBV infection, LC and HCC.

Highlights

Hepatitis B virus (HBV) infection is still a threat to health worldwide causing chronic infection among 250 million individuals (Lee and Banini, 2019)
The pathogenesis of HBV infection is rather complicated, which is influenced by several factors including HBV genotype, viral variation and replication
Previous studies demonstrated that IL-35 showed inhibitory effects on the HBV-specific cytotoxic T lymphocyte (CTL) response, which affected HBV clearance and modulated the pathogenesis of hepatocellular carcinoma (HCC) (Li et al, 2015; Xiang and Xie, 2015; Xue et al, 2019)

Summary

INTRODUCTION

Hepatitis B virus (HBV) infection is still a threat to health worldwide causing chronic infection among 250 million individuals (Lee and Banini, 2019). There is growing evidence that cytokine-mediated immune responses play an important role in determining clinical outcomes during HBV viral control and virus-induced hepatic injury (Dandri and Locarnini, 2012; Seetharam et al, 2014; Li et al, 2016). IL-35 can induce the generation of iTr35, Bregs and possibly CD8+ Tregs, which function as an immunosuppressive factor in immune mediated progression of chronic hepatitis B. Previous studies demonstrated that IL-35 showed inhibitory effects on the HBV-specific CTL response, which affected HBV clearance and modulated the pathogenesis of HCC (Li et al, 2015; Xiang and Xie, 2015; Xue et al, 2019). Each of IL-12 family members (e.g., IL-12, IL-23, IL-27, and IL-39) is a heterodimeric cytokine composed of α chain (i.e., p19, p28, and p35) and β chain including p40 and Epstein-Barr virus-induced gene 3 [EBI3], which contain common subunits

Normalization No liver damage

Lead to imbalance of immune response and contribute to viral persistence

Findings

CHALLENGES AND PROSPECTS