Abstract
Primary biliary cholangitis (PBC) is a chronic liver autoimmune disease with augmented T helper (Th) 1 and corresponding cytokine IFN-γ immune responses. Using 2-octynoic acid (2-OA) coupled to OVA (2-OA-OVA)-induced mouse models of autoimmune cholangitis (inducible chemical xenobiotic models of PBC), our previous study demonstrated that overexpression of IFN-γ in the model mice enhanced liver inflammation upon disease initiation, but subsequently led to the suppression of chronic inflammation with an increase in interleukin-30 (IL-30) levels. In this study, we investigated whether IL-30 had an immunosuppressive function and whether it could be part of an immune therapeutic regimen for PBC, by treating model mice with murine IL-30-expressing recombinant adeno-associated virus (AAV-mIL-30). We first defined the effects of AAV-mIL-30 in vivo by administering it to a well-known concanavalin A (ConA)-induced hepatitis model of mice and found that AAV-mIL-30 reduced the numbers of activated CD25+CD4+ T cells and the levels of serum IFN-γ and IL-12. In autoimmune cholangitis, decreased numbers of activated CD4+ T cells and Foxp3+ regulatory T cells were noted in the mice treated with AAV-mIL-30 at 3 weeks after the 2-OA-OVA immunization. Treatment with IL-30 did not change the features of autoimmune cholangitis including autoantibodies, cell infiltration, and collagen deposition in the liver at 11 weeks of examination. However, increased levels of cytokines and chemokines were observed. These results suggest that IL-30 suppresses not only CD4+ T cells but also regulatory T cells. Additionally, the administration of IL-30 did not suppress liver inflammation in the murine model of PBC.
Highlights
Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease characterized by the immune-mediated destruction of intrahepatic small bile ducts, leading to decreased bile secretion, fibrosis, and eventual liver failure
By using the chemical xenobiotic 2-octynoic acid (2-OA) coupled to the OVA (2-OA-OVA)-induced PBC mouse model, we demonstrated that the overexpression of IFN-γ enhanced liver inflammation and caused the onset of disease by increasing immune cell infiltrates, upregulating MHC class II expression of antigen-presenting cells
Our results showed that IL-30 suppressed the numbers of CD4+ T cells and regulatory T cells (Tregs) and IL-30-induced increased inflammation in the mouse model of PBC
Summary
Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease characterized by the immune-mediated destruction of intrahepatic small bile ducts, leading to decreased bile secretion, fibrosis, and eventual liver failure. The destruction of biliary cells is mediated by liver-infiltrating autoreactive T cells [1,2]. There are a significantly higher number of IFN-γ mRNApositive cells within the livers of PBC patients than in those of healthy individuals [3,4,5]. In experimental mouse models of PBC, there are significantly increased levels of Th1 cytokines, TNF-α and IFN-γ, in the liver [11,12,13]. The deletion of IFN-γ in a PBC mouse model reduces inflammatory portal infiltrates associated with the prevention of bile duct damage [10]
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