Interleukin-35 Level Is Reduced in Patients with Chronic Hepatitis B Virus Infection

Cheng, Sheng-Tao; Yuan, Ding; Liu, Yi; Huang, Ying; Chen, Xiang; Yu, Haibo; He, Lin; Jiang, Hui; Ren, Ji-Hua; Chen, Juan

doi:10.7150/ijms.21957

Cited by 14 publications

(12 citation statements)

References 37 publications

(36 reference statements)

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“…The predominant mechanism of suppression was to inhibit proliferation and effector activities of T cells, thus, might be a potential therapeutic target for controlling HBV infection [19]. Both serum IL-35 and IL-35 mRNA in CD4 + T cells was elevated in chronic HBV infection, and was associated with viral replication and hepatocytes damage [36, 37]. Recombinant IL-35 stimulation not only directly increased HBV transcription and replication in vivo [38], but also suppressed HBV core-specific interferon-γ-secreting CD8 + T cells in vitro [39].…”

Section: Discussionmentioning

confidence: 99%

Interleukin-35 modulates the balance between viral specific CD4+CD25+CD127dim/- regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection

Yang

Jia

Shao

et al. 2019

Virol J

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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 + CD127 dim/− 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.

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Section: Discussionmentioning

confidence: 99%

Interleukin-35 modulates the balance between viral specific CD4+CD25+CD127dim/- regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection

Yang

Jia

Shao

et al. 2019

Virol J

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“… 48 Significantly, T reg cells are an important regulator of infectious tolerance via the ability to convert T conv cells into iT reg cells directly by producing suppressive cytokines, such as IL-10, TGF-β, or the newly identified IL-35. 44 iTr35 cells showed stronger and more durable immunosuppression than T reg cells. 49 Thus, while T reg cells play a fundamental role in the maintenance of immune tolerance to prevent autoimmune disease, T h 17 cells play the opposite role.…”

Section: Potential Relationship Between Il-35 and Itpmentioning

confidence: 89%

“… 25 The elevated IL-35 levels in chronic hepatitis B enhanced the suppressive function of CD4+CD25+ T reg cells, while reduced cytolytic and noncytolytic activity of hepatitis B antigen-specific CD8+ T cells, which might be due to the direct response and positive feedback mechanisms of T reg cells to IL-35. 44 Research shows that IL-35 suppresses the expansion of CTLs and inhibits antigen-specific IFN-γ secretion by CTLs. 45 In addition, IL-35 may inhibit the proliferation of effector T cells by blocking the cell cycle, causing G1 phase arrest and inhibiting the proliferation of immature T cells.…”

Section: Potential Relationship Between Il-35 and Itpmentioning

confidence: 99%

Immunomodulatory cytokine interleukin-35 and immune thrombocytopaenia

Zhu

Shan

2020

J Int Med Res

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Considerable attention has been paid to interleukin (IL)-35 because of its immunosuppressive effects in a variety of autoimmune diseases. IL-35, a recently identified cytokine of the IL-12 family, is a negative regulatory factor secreted by IL-35-inducible regulatory T cells (iTr35 cells) and the recently reported regulatory B cells (Breg cells). Four biological effects of IL-35 have been discovered in vitro and in vivo: (i) suppression of T cell proliferation; (ii) conversion of naive T cells into iTr35 cells; (iii) downregulation of type 17 helper T (Th17) cells; and (iv) conversion of Breg cells into a Breg subset that produces IL-35 and IL-10. IL-35 plays an important role in a variety of autoimmune diseases, such as rheumatoid arthritis, allergic asthma and systemic lupus erythematosus. Primary immune thrombocytopaenia (ITP), which is characterized by isolated thrombocytopaenia and mild mucocutaneous to life-threatening bleeding, is an autoimmune disease with complex dysregulation of the immune system. Both antibody-mediated and/or T cell-mediated platelet destruction are key processes. In addition, impairment of T cells and cytokine imbalances have now been recognized to be important. This review summarizes the immunomodulatory effects of IL-35 and its role in the pathogenesis of ITP as mediated by T and B cells.

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“…Eighty cases (50 males and 30 females) with chronic HBV infection were recruited from the Specialized Center for Gastroenterology and Hepatology (SCGH) in Baghdad. The WHO and European Association for the Study of the Liver (EASL) guidelines on HBV testing were followed [16,17]. Accordingly, anti-HBc (hepatitis B core antigen), IgM, -HBc IgG and -HbsAg (hepatitis B surface antigen) antibodies were determined.…”

Section: Patients and Controlmentioning

confidence: 99%

Serum Level of Interleukin-35 in Patients with Chronic Hepatitis B Virus Infection

Al-azzawi

Mohsen

Ad’hiah

2020

eijs

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Interleukin-35 (IL-35) is a new member of IL-12 family of cytokines, and its role in pathogenesis of hepatitis B virus (HBV) infection has been recently suggested. Accordingly, a case-control study was conducted during June - October 2018 to determine IL-35 serum level in Iraqi patients with chronic HBV infection. The results revealed that IL-35 level was significantly decreased in patients as compared to control (163 vs. 301 pg/ml; p < 0.001). However, such decreased level was more pronounced in patients at the age groups < 40 and 40 – 50 years (165 and 145 pg/ml, respectively) as compared to the corresponding age groups in control (482 and 234 pg/ml, respectively). In the case of gender groups, both male and female patients showed a significantly decreased level of IL-35 compared to the corresponding control groups (163 and 163 vs. 306 and 297 pg/ml; p = 0.004 and 0.001, respectively). Distributing HBV patients and control according to medians of IL-35 (≤ median and > median) revealed that 67.5% of patients had ≤ median compared to 35.4% among control. Such difference was significant (p < 0.001), with a scored odds ratio (OR) of 3.79. Receiver operating characteristic (ROC) analysis revealed that the decreased level of IL-35 occupied an area under curve (AUC) of 0.710, which was highly significant (p < 0.001). At a cut-value of 188 pg/ml or lower, the diagnostic sensitivity and specificity were 67.7 and 66.2%, respectively. In conclusion, these results confirmed the role of IL-35 in the pathogenesis of HBV

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Interleukin-35 Level Is Reduced in Patients with Chronic Hepatitis B Virus Infection

Cited by 14 publications

References 37 publications

Interleukin-35 modulates the balance between viral specific CD4+CD25+CD127dim/- regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection

Interleukin-35 modulates the balance between viral specific CD4+CD25+CD127dim/- regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection

Immunomodulatory cytokine interleukin-35 and immune thrombocytopaenia

Serum Level of Interleukin-35 in Patients with Chronic Hepatitis B Virus Infection

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