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Interleukin-35 (IL-35) is a newly identified inhibitory cytokine. It has recently been found to play an extremely important role in chronic hepatitis B disease, which makes it likely to be a target for new therapies for hepatitis B malady. IL-35 modulates a variety of immune mechanisms to cause persistent viral infections, such as affecting the ratio of helper T cells, reducing the activity of cytotoxic T cells, hindering the antigen presentation capacity for dendritic cells, and increasing the transcription level of hepatitis B virus. On the other hand, IL-35 can control the inflammation caused by hepatitis B liver injury. Therefore, to seek a breakthrough in curing hepatitis B disease, the contradictory part of IL-35 in the occurrence and development of this sickness is worthy of further discussion and research. This article will systematically review the biological effects of IL-35 and the specific mechanisms affecting the disease. [ABSTRACT FROM AUTHOR]

Background: Interleukin (IL)-35 regulates imbalance between regulatory T cells (Tregs) and T helper (Th) 17 cells, leading to an important modulator in autoimmune disorder, cancer, and infectious diseases. Our previous study revealed an immunosuppressive activity of IL-35 in chronic hepatitis B virus (HBV) infection. Thus, the aim of the current study was to investigate the role of regulatory function of IL-35 to viral specific Tregs/Th17 cells balance in chronic HBV infection. Methods: A total of 44 HLA-A2 restricted chronic HBV infected patients, including 21 of chronic hepatitis B (CHB) and 23 of asymptomatic HBV carriers (ASC) were enrolled. Purified CD4+ T cells or CD4+CD25+CD127dim/− Tregs were stimulated with recombinant IL-35. HBV core antigen specific Tregs and Th17 cells were determined by flow cytometry. FoxP3 and RORγt mRNA was measured by real-time PCR. Cytokines production (IL-10 and IL-17) was investigated by ELISA. Results: Peripheral viral specific Tregs was comparable between CHB and ASC. However, increased percentage of viral specific Th17 cells was found in CHB, leading to the reduction of Tregs/Th17 ratio in CHB patients. IL-35 stimulation elevated viral specific Tregs, but not Th17 cells frequency, in both CHB and ASC, resulting in the elevation of Tregs/Th17 ratio in both groups. This process was accompanied by increased expression of FoxP3 mRNA and IL-10 production, and decreased IL-17 secretion and STAT3 phosphorylation in purified CD4+ T cells. Moreover, IL-35 stimulation inhibited viral specific Th17-like phenotype differentiation from Tregs in CHB patients. Effective anti-HBV therapy did not affect viral specific Tregs/Th17 cells frequency or IL-35 expression in CHB patients, however, reduced responsiveness of CD4+ T cells or Tregs to IL-35 stimulation in vitro. Conclusion: Our findings indicated that IL-35 regulation to viral specific Tregs/Th17 balance may contribute to viral persistence in chronic HBV infection. [ABSTRACT FROM AUTHOR]

• NKB cells was down-regulated in HCC. • NKB cells promoted cytotoxicity of CD8+ T cells via IL-18 secretion. • IL-35 down-regulated NKB cell percentage and IL-18 production. • IL-35 suppressed NKB cell-mediated CD8+ T cell cytotoxicity in HCC. Natural killer-like B (NKB) cells are newly identified lymphocyte subset, which present immunomodulatory property in infectious diseases through secretion of interleukin-18 (IL-18). However, the role of NKB cells function and its regulation in hepatocellular carcinoma (HCC) is not elucidated. Seventy-two HCC patients and twenty-five controls were enrolled. Peripheral and liver-infiltrating CD3-CD19+CD56+NKp46+ cells were investigated by flow cytometry. Serum IL-35 and NKB cell-secreting cytokine level was measured by ELISA. The regulatory activity of IL-35 to peripheral and liver-infiltrating NKB cells was assessed in direct co-culture system between CD8+ T cells and HepG2 cells. Peripheral NKB cells and IL-18 secretion were reduced in HCC patients, while liver-infiltrating NKB cells and IL-18 secretion were also decreased in HCC tumor sites. Increased IL-35 level was negatively correlated with NKB cell percentage and IL-18 production in HCC. NKB cells induced the elevation of CD8+ T cell cytotoxicty, and this enhancement could be inhibited by IL-18 binding protein. IL-35 stimulation dampened NKB cell percentage and IL-18 production, leading to the suppression of NKB cell-mediated CD8+ T cell cytotoxicity in HCC patients. Our current data revealed that IL-35 might suppress NKB cell activity in HCC patients. [ABSTRACT FROM AUTHOR]

• Plasma and ascitic IL-35 was elevated in SBP. • Ascitic CD8+ T cells exhibited exhausted phenotype in SBP. • IL-35 suppressed cytotoxicity of ascitic CD8+ T cells. • IL-35 suppressed cytotoxic molecules expression in ascitic CD8+ T cells. • IL-35 promoted immune-checkpoint molecules expression in ascitic CD8+ T cells. Interleukin (IL) -35 induces immunotolerance by suppression of CD8+ T cells during chronic infections and cancers. In the present study, we amined to investigate the role of IL-35-mediated regulation of CD8+ T cells in patients with liver cirrhosis. Seventy-one patients with liver cirrhosis (46 patients with untainted ascites and 25 patients with spontaneous bacterial peritonitis [SBP]) and 22 controls were enrolled. Plasma and ascitic IL-35 levels were measured using ELISA. Peripheral and ascitic CD4+ and CD8+ T cells were purified to investigate their functional phenotypes. IL-35-stimulated CD8+ T cells were cultured with HepG2 cells in direct and indirect contact systems. Lactate dehydrogenase expression and cytokine secretion were measured to determine the cytotoxicity of CD8+ T cells. Plasma IL-35 was elevated in patients with liver cirrhosis, and ascitic IL-35 levels were higher in the SBP group than in the untainted ascites group. No significant differences in transcription factor expression or cytokine production in peripheral and ascitic CD4+ T cells were observed among groups. In the SBP group, ascitic CD8+ T cells expressed decreased cytotoxic molecules, along with the reduced secretion of interferon-γ and tumor necrosis factor-α when compared with the untainted ascites group. IL-35 stimulation suppressed ascitic CD8+ T cell cytotoxicity and cytokine production in both direct and indirect contact culture systems. This process was accompanied by decreased cytotoxic molecule expression and increased immune-checkpoint molecules in ascitic CD8+ T cells. The present findings revealed that overexpression of ascitic IL-35 dampened the cytotoxicity of CD8+ T cells in liver cirrhotic patients with SBP. [ABSTRACT FROM AUTHOR]