Endogenous IL-10 maintains immune tolerance but IL-10 gene transfer exacerbates autoimmune cholangitis

Abstract

The immunomodulatory effect of IL-10 as an immunosuppressive and anti-inflammatory cytokine is well known. Taking advantage of our established mouse model of autoimmune cholangitis using 2-octynoic acid conjugated ovalbumin (2-OA-OVA) induction, we compared liver pathology, immune cell populations and antimitochondrial antibodies between IL-10 knockout and wild type mice immunized with 2-OA-OVA. At 10 weeks post immunization, portal inflammation and fibrosis were more severe in 2-OA-OVA immunized IL-10 knockout mice than in wild type mice. This was accompanied by significant higher levels of collagen I and III expression, T, NK and NKT subsets in liver and IgG anti-mitochondrial autoantibodies (AMA) compared to 2-OA-OVA immunized wild type mice, suggesting that endogenous IL-10 is necessary for the maintenance of immune tolerance in primary biliary cholangitis (PBC). Further, we investigated whether administration of exogenous IL-10 could prevent PBC by administration of IL-10 expressing recombinant adeno-associated virus (AAV-IL-10) either 3 days before or 3 weeks after the establishment of liver pathology. Interestingly, administration of AAV-IL-10 resulted in increased liver inflammation and fibrosis, accompanied by increases in IFN-γ in liver CD4+ T cell, granzyme B, FasL, and CD107a in liver CD8+ T and NKT cells, and granzyme B and FasL in liver NK cells of AAV-IL-10 administered mice compared with control mice. Furthermore, administration of AAV-IL-10 significantly increased levels of proinflammatory cytokines and chemokines (IFN-γ, TNF-α, CXCL9 and CXCL10) and collagen I and III production in naive mice, together with increase in immune cell infiltration and collagen deposition in the liver, suggesting a role of IL-10 in fibrosis. In conclusion, our data demonstrate that endogenous IL-10 is critical in the maintenance of immune tolerance but exogenous administration of IL-10 exacerbates liver inflammation and fibrosis. Furthermore, the distinctive presence of inflammatory immune cell populations and collagen expression in AAV-IL-10 treated naive mice cautions against the clinical use of exogenous IL-10 in patients with autoimmune cholangitis.

An association between elevated telomerase reverse transcriptase expression and the immune tolerance disruption of dendritic cells

“…DCs interact with a variety of immune cells to regulate the activities of other immune cells [ 25 ]. The reduction of the IL-10 expression suggests a dysfunctional state of immune regulatory cells [ 23 , 26 ]. A novel point of the present study is that we found an overexpression of Tert in DCs of subjects with AR, which could disrupt the tolerogenic feature of TolDCs.…”

Chimonanthus nitens Oliv Polysaccharides Modulate Immunity and Gut Microbiota in Immunocompromised Mice

“…TNF-α is an important mediator of immune protection, promoting cell proliferation and differentiation and enhancing the killing ability of killer cells such as T cells. IL-10 is generally considered as a protective cytokine that promotes immune regulation, and IL-17 is involved in host defense against fungi, extracellular bacteria, and other eukaryotes [39,40]. Previous studies have shown that the effects of polysaccharides on improving immune function are closely associated to their ability to promote cytokine secretion [3,[41][42][43][44].…”

Reply to: “A spotlight on natural killer cells in primary biliary cholangitis”

“…We agree with Dr Hydes and Prof. Khakoo on the relevance of NK cells in bridging innate with adaptive immunity in PBC, with one characteristic being enhanced interferon (IFN)-c, other than IL-10, production. 4,5 In particular, NK cell cytotoxicity against biliary epithelial cells (BECs) is initiated only after toll-like receptor (TLR) 3-mediated NK stimulation and TLR4-mediated monocyte stimulation. This function is regulated by a large family of inhibitory NK cell receptors, including killer-cell immunoglobulin-like receptors and C-lectin type molecules, which recognize major histocompatibility complex (MHC) class I present on autologous cells.…”