IL‐35: A potential therapeutic target for controlling hepatitis B virus infection

Abstract

Interleukin (IL)-35, a recently identified cytokine of the IL-12 family, is a potent immunosuppressive cytokine secreted by regulatory T (Treg) cells and the newly reported regulatory B (Breg) cells. IL-35 functions as a crucial immunosuppressive factor in immune-mediated diseases, and the predominant mechanism of suppression is its ability to suppress T cell proliferation and effector functions. The pathogenic processes of the non-cytopathic hepatitis B virus (HBV) infection-related liver diseases are immune-mediated, including liver damage and viral control. It has been found that IL-35 is detectable in peripheral CD4(+) T cells in chronic HBV-infected patients, whereas it is undetectable in healthy individuals. There is growing evidence that cytokine-mediated immune responses play a pivotal role in determining the clinical outcome during HBV infection. It is particularly important to investigate the effects of IL-35 in the immunopathogenesis of chronic HBV infection. In this study, the recent understanding of this issue is discussed.

IL-35 expression in hepatocellular carcinoma cells is associated with tumor progression

“…As an anti-inflammatory and immune inhibitory cytokine, IL-35 has been demonstrated to suppress T cell proliferation [1], convert naive T cells into IL-35-producing iTr35 [8], and play important roles in inflammatory diseases [9–10], infectious diseases [5, 11–12], autoimmune diseases [13–16], and allograft rejection [17–18]. …”

Inhibition of cardiac allograft rejection in mice using interleukin‐35‐modified mesenchymal stem cells

“…We infected MSCs with lentiviral vectors overexpressing the IL‐35 gene and found that IL‐35‐MSCs can continuously and stably secrete IL‐35in vivo and in vitro. This result may have been due to the ability of MSC‐secreted IL‐35 to stimulate the proliferation of iTr35, which further promoted IL‐35 secretion to ensure its stable expression in vitro and in vivo . More importantly, compared with MSC monotherapy, IL‐35‐MSCs were more effective at relieving graft rejection and prolonging graft survival in the mouse model of heterotopic abdominal heart transplantation.…”

“…In addition, IL‐35 can also induce the transformation of conventional T cells (Tconv) into Tregs, allowing these Tregs (iTr35) to once again secrete IL‐35 . This positive feedback cascade amplification effect greatly inhibits the effects of multiple effector cells and cytokines . For example, IL‐35 could inhibit the promotion of T helper 1 (Th1) and Th17 cell differentiation and function, which relieves the symptoms of collagen‐induced arthritis, and accumulating evidence indicates that IL‐35 plays an important role in the occurrence and development of various autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis and systemic lupus erythaematosus .…”

Gene Expression and Antiviral Activity of Interleukin-35 in Response to Influenza A Virus Infection

“…IL-35 is detectable in peripheral CD4 ϩ T cells and is believed to play important functions in inhibition of the immune response during chronic HBV infection (56), suggesting it may be a potential therapeutic target to control HBV infection (29). Thus, we investigated the biological function of virus-induced IL-35 expression.…”