IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: Implications for therapy

Abstract

The interleukin (IL)-12/IL-23 mediated Th1/Th17 signaling pathway has been associated with the etiopathogenesis of primary biliary cirrhosis (PBC). To address the cytokine microenvironment specifically in the liver, we examined the localized expression of cytokine subunits and their corresponding receptors using previously optimized immunohistochemistry with an extensive panel of antibodies directed at IL-12p70, IL-12p35, IFN-γ, IL-12RB2, IL-23p40, IL-23p19, IL-17 and IL-23R using liver from PBC (n=51) and non-PBC (n=80) control liver disease patients. Multiple portal tracts in each patient were blindly evaluated and individually scored. We report herein that although IL-12/Th1 and IL-23/Th17 staining were detected in all of the liver sections, they were primarily localized around the damaged interlobular bile ducts in PBC. Most importantly, Th17 skewing was prominent in advanced PBC patients with intensive secretion of IL-23p19 by inflamed hepatocytes around IL-23R, IL-12RB2, and IFN-γ expressing degenerated cholangiocytes. Our novel finding on the direct association of Th17 skewing and disease severity illustrates the significance of the IL-23/Th17 pathway in the perpetuation of IL-12/Th1-mediated immunopathology in PBC. Furthermore, localized IL-23p19 production by hepatocytes may enhance pro-fibrotic Th17 signaling and pro-inflammatory IFN-γ production that contribute to PBC pathology. In conclusion, our data emphasize the pathogenic relevance of IL-12/Th1 and IL-23/Th17 in the evolution of PBC. Of significance, however, the shift from a Th1 to a Th17 imbalance at advanced stages of the disease suggests the necessity to consider modulation of the IL-23/Th17 pathway as a potential target for therapeutic intervention.

Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

“…+ and CD8 + T cells are noted in the liver of both patients with PBC and murine models of autoimmune cholangitis [5][6][7]15,18,[25][26][27][28][29][30][31][32]. In this study, 2-OA-BSA/α-GalCer-immunized mice had significant increases in CD4 + and CD8 + T cells.…”

Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis

“…IL-35 was shown to signal through STAT1 or STAT4 after binding to gp130 or IL12Rβ2 on T cells (Collison et al 2012). Liver samples from patients with PBC showed strong staining for IL12Rβ2 and IFN-γ in the early stage and IL-23 and IL-17 in the late stage of disease (Yang et al 2014a). Exposure to IFN-γ upregulated expression of IL12Rβ2, leading to a positive feedback loop in response to antigen stimulus (Webb et al 2015).…”

Primary Biliary Cholangitis: Its Pathological Characteristics and Immunopathological Mechanisms

“…Previous studies described the profiles of inflammatory cells surrounding bile ducts in PBC (9,(14)(15)(16)(17). Cellular profiles may change depending on the process of biliary inflammation.…”

“…In the early stage, a Th1-predominant cytokine milieu is characteristic in CNSDC (22) ; however, as the disease progresses, IL-12/Th1 and IL-23/Th17 cells both appear to varying extents. In the late stage of PBC, the ratio of cell formation shifts from Th1 cells to Th17 cells (16). A decreased number of portal-infiltrating regulatory T cells and an imbalanced ratio with cytotoxic T cells may be associated with disease progression (15,23).…”