TABLE 1.
Important cytokines and chemokines in HBV infection.
| Mediatores | Primary effects | Roles in HBV infection | References |
|---|---|---|---|
| Cytokines | |||
| IL-1 | Proinflammatory | Predictor of treatment response to IFN-α | Lei et al., 2019 |
| IL-2 | T cell proliferation, NK cell cytolytic activity; promotes Tregs development and suppressive activity | Evaluation of HBV-specific T cell functions; immunomodulatory agent enhancing host immune activity | Chokshi et al. (2014); Tan et al. (2018) Onji et al. (1987) |
| IL-4 | Promotes Th2 cells differentiation and humoral immunity | Suppresses the expression and replication of HBV in different HCC lines; downregulated in CHB patients | Lin et al. (2003); Yao et al. (2011); Gu et al. (2019) |
| IL-6 | Pleiotropic actions that affect the functions of a variety of lymphoid cells | Inhibits HBV entry and transcription; manipulates the development of LC and HCC | Palumbo et al. (2015); Chang et al. (2015); Kao et al. (2015); Zhou et al. (2018) |
| IL-12 | Promotes cellular immunity and modulates the cytotoxic activity of CLTs and NK cells | Enhances the anti-virus properties of cytotoxicity, polyfunctionality, and multispecificity of HBV-specific T cells; combination treatment with IL-12 favors HBV clearence | Xiong et al. (2007); Wu et al. (2015); Zeng et al. (2013); Carreno et al. (2000) |
| IL-21 | B cell differentiation, germinal center responce and antibodies production | Boosts and sustains HBV-specific CD8+ T cell effects by enhancing both cytolytic and noncytolytic pathways; associated with age-dependent outcome and vertical transmission of HBV infection | Li et al. (2015); Shen et al. (2021) Publicover et al. (2011); Vyas et al. (2019); Wang et al. (2021) |
| IL-17 | Proinflammatory | Suppresses HBV replication in a noncytopathic manner; involved in the pathogenesis of liver damage, LC and HCC | Wang et al. (2013a); Bao et al. (2017) |
| IL-22 | Tissue regeneration | Exerts dual effects in the context of inflammation | McAleer and Kolls. (2014) |
| IL-23 | Stimulation of DC antigen presentation, generation, and maintenance of Th17 cells | Amplifies Th17 cell responses and liver inflammation; alters macrophage function and shapes a pro-cancer milieu for HCC | McKenzie et al. (2006); Wang et al. (2013b); Zang et al. (2018) |
| IFN | Control viral replication and dissemination | IFN-α exerts both direct antiviral and host immunomodulation effects and is the current standard treatment of HBV | Biron (2001); Sadler and Williams (2008) |
| HBV specific IFN-γ producing T cells are associated with viral clearance | Wang et al. (2020) | ||
| TNF-α | Proinflammatory | Mediator of anti-HBV immunity, induces liver inflammation, leads to liver fibrosis | Wang et al. (2020) |
| IL-10 | Regulatory cytokine, anti-inflammatory | Circulating IL-10+ Bregs and Tfr cells are associated with poor virus eradication and liver injury in CHB; IL-10-producing Breg cells suppress HBV-specific CD4+ and CD8+ T cell responses but enhance Treg cells | Wang et al. (2014); Das et al. (2012) |
| IL-35 | Exerts an immunosuppressive effect on T cells | Elevates viral-specific Tregs, IL-10 production, decreases IL-17 secretion and contributes to viral persistence | Yang et al. (2019) |
| TGF-β | Anti-inflammatory cytokine, regulates diverse cellular processes | Boosting the activities of Treg cells; contributes to all stages of liver disease progression | Karimi-Googheri et al. (2014); Dooley and ten Dijke, (2012) |
| Chemokines | |||
| CXCL9, CXCL10, CXCL11 | Ligands of CXCR3, key immune chemoattractants during IFN-induced inflammatory response | Serum CXCL9, CXCL10, CXCL11 are elevated in CHB patients; CXCL10 enhances the migration of peripheral leukocytes into the liver; useful predictive indicators of disease progress and treatment response | Kakimi et al. (2001); Keating et al. (2014); Zhou et al. (2010); Sonneveld et al. (2013); Guo et al. (2016); Lee et al. (2013a) |
| CXCL13 | Ligands of CXCR5, involed in the onset and maintenance of humoral immunity | Favors the recruitment of CD19+ B cells and CXCR5+CD8+ T cells into the liver; plasma CXCL13 serve as a biomarker for GC activity; increased plasma CXCL13 is distinctly observed in patients who achieve immune control of CHB infection | Li et al. (2020), (Havenar-Daughton et al., 2016), (Liu et al., 2017b) |
| CXCL8 | Proinflammatory signaling cascade and guides neutrophils to infection site | Associated with the severity of liver inflammation/fibrosis and resistance to IFN-α therapy | Yang et al. (2014) |
| CXCL12 | Strong chemotaxis for lymphocytes | Involved in recruitment and retention of immune cells in CHB patients with advanced liver fibrosis | Wald et al. (2004) |
HBV, hepatitis B virus; IL, interleukin; IFN, interferon; NK, natural killer; Treg, T regulatory; Th, T helper; HCC, hepatocellular carcinoma; CHB, chronic hepatitis B; LC, liver cirrhosis; CTLs, cytotoxic T lymphocytes; DC, dendritic cells; TNF, tumor necrosis factor; Bregs, B regulatory cells; Tfr, T follicular regulatory; TGF, transforming growth factor.