Hepatic IL-17 responses in human and murine primary biliary cirrhosis

Abstract

The emergence of new regulatory and pro-inflammatory immune cell subsets and cytokines dictates the need to re-examine the role of these subsets in various diseases involving the immune system. IL-17 has been recently identified as a key cytokine involved in numerous autoimmune processes. However, its role in liver autoimmune diseases remains unclear. Primary biliary cirrhosis (PBC) is characterized histologically by autoreactive CD4 and CD8 T cells surrounding damaged bile ducts. CD4+ T cells are a major source of IL-17, which compose a distinct T helper subset (Th17). Thus we set out determine the role of IL-17 in both human and a murine model of PBC in a liver-targeted manner. Our data demonstrate an increase in the frequency of IL-17+ lymphocytic infiltration in liver tissues from PBC patients and those with other liver dysfunctions as compared to healthy livers. IL-2 receptor α knockout mice, a recently identified murine model of human PBC, also demonstrate marked aggregations of IL-17 positive cells within portal tracts and increased frequencies of Th17 cells in the liver compared to the periphery. Interestingly, CD4+ T cells from livers of normal C57BL/6J mice also secreted higher levels of IL-17 relative to those from spleens, indicating a preferential induction of Th17 cells in liver tissues. Importantly, C57BL/6J cocultures of splenic CD4+ T cells and liver non-parenchymal cells increased IL-17 production approximately 10 fold compared to T cells alone, suggesting a role of the liver microenvironment in Th17 induction in cases of liver autoimmunity and other liver inflammatory diseases.

Interleukin-17A-Induced Epithelial-Mesenchymal Transition of Human Intrahepatic Biliary Epithelial Cells: Implications for Primary Biliary Cirrhosis

“…Thus, IL-17A was elevated in PBC patients compared with healthy controls. Our data confirmed similar findings in previous studies in PBC patients (Lan et al 2009;Qian et al 2013).…”

“…Previous studies showed that frequencies of IL-17A-positive lymphocytic cells were increased in the liver from PBC patients (Lan et al 2009) and IL-17A expression was elevated in peripheral blood of PBC patients (Qian et al 2013). Additionally, IL-17A induced EMT of epithelial cells (Mi et al 2011;Ji et al 2013;Vittal et al 2013).…”

“…Interleukin-17 (IL-17A), a typical pro-inflammatory cytokine, has recently been shown to induce EMT of alveolar epithelial cells (Mi et al 2011) and bronchial epithelial cells (Ji et al 2013;Vittal et al 2013). Interestingly, fre-quencies of IL-17A -positive lymphocytic cells are increased in the liver of PBC patients (Lan et al 2009) and IL-17A expression is elevated in peripheral blood of PBC patients (Qian et al 2013). However, the association between IL-17A and IBECs-EMT and their roles in the pathogenesis of PBC remain unclear.…”

Th-17 cells infiltrate the liver in human biliary atresia and are related to surgical outcome

“…Interestingly, we have found a two-fold difference in Th-17 counts between patients who failed to achieve a normal bilirubin level post-KPE and those who did. However, just as the cause of biliary atresia can be heterogenous, so the response to the KPE is also multifactorial and caution should be exerted in the interpretation of a single observation, particularly when cellular in nature (13,38,29). In our previous immunohistochemical studies we reported that a liver infiltrate characterized by lower numbers of macrophages (CD68+) at the time of surgery was correlated to better outcomes at one year in 28 children with BA (13).…”

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

“…Functionally, autoreactive CD8 T cells in PBC have specific cytotoxicity against PDC-E2 antigen as well as the ability to produce interferon-c rather than IL-4/IL-10 cytokines, 83 while IL-17 has been recently suggested to play a role in PBC. 84 …”