TY - JOUR
T1 - Hydrophobic bile acids suppress expression of AE2 in biliary epithelial cells and induce bile duct inflammation in primary biliary cholangitis
AU - Hisamoto, Satomi
AU - Shimoda, Shinji
AU - Harada, Kenichi
AU - Iwasaka, Sho
AU - Onohara, Shinya
AU - Chong, Yong
AU - Nakamura, Minoru
AU - Bekki, Yuki
AU - Yoshizumi, Tomoharu
AU - Ikegami, Toru
AU - Maehara, Yoshihiko
AU - He, Xiao Song
AU - Gershwin, M. Eric
AU - Akashi, Koichi
N1 - Funding Information:
Financial support provided by Grant-in-Aid for Scientific Research (C) (Kakenhi 26461012 ) and National Institutes of Health grant, DK39588 (MEG).
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Understanding the mechanisms of chronic inflammation in primary biliary cholangitis (PBC) is essential for successful treatment. Earlier work has demonstrated that patients with PBC have reduced expression of the anion exchanger 2 (AE2) on biliary epithelial cells (BEC) and deletion of AE2 gene has led to a PBC-like disorder in mice. To directly address the role of AE2 in preventing PBC pathogenesis, we took advantage of our ability to isolate human BEC and autologous splenic mononuclear cells (SMC). We studied the influence of hydrophobic bile acids, in particular, glycochenodeoxycholic acid (GCDC), on AE2 expression in BEC and the subsequent impact on the phenotypes of BEC and local inflammatory responses. We demonstrate herein that GCDC reduces AE2 expression in BEC through induction of reactive oxygen species (ROS), which enhances senescence of BEC. In addition, a reduction of AE2 levels by either GCDC or another AE2 inhibitor upregulates expression of CD40 and HLA-DR as well as production of IL-6, IL-8 and CXCL10 from BEC in response to toll like receptor ligands, an effect suppressed by inhibition of ROS. Importantly, reduced AE2 expression enhances the migration of autologous splenic mononuclear cells (SMC) towards BEC. In conclusion, our data highlight a key functional role of AE2 in the maintenance of the normal physiology of BEC and the pathogenic consequences of reduced AE2 expression, including abnormal intrinsic characteristics of BEC and their production of signal molecules that lead to the chronic inflammatory responses in small bile ducts.
AB - Understanding the mechanisms of chronic inflammation in primary biliary cholangitis (PBC) is essential for successful treatment. Earlier work has demonstrated that patients with PBC have reduced expression of the anion exchanger 2 (AE2) on biliary epithelial cells (BEC) and deletion of AE2 gene has led to a PBC-like disorder in mice. To directly address the role of AE2 in preventing PBC pathogenesis, we took advantage of our ability to isolate human BEC and autologous splenic mononuclear cells (SMC). We studied the influence of hydrophobic bile acids, in particular, glycochenodeoxycholic acid (GCDC), on AE2 expression in BEC and the subsequent impact on the phenotypes of BEC and local inflammatory responses. We demonstrate herein that GCDC reduces AE2 expression in BEC through induction of reactive oxygen species (ROS), which enhances senescence of BEC. In addition, a reduction of AE2 levels by either GCDC or another AE2 inhibitor upregulates expression of CD40 and HLA-DR as well as production of IL-6, IL-8 and CXCL10 from BEC in response to toll like receptor ligands, an effect suppressed by inhibition of ROS. Importantly, reduced AE2 expression enhances the migration of autologous splenic mononuclear cells (SMC) towards BEC. In conclusion, our data highlight a key functional role of AE2 in the maintenance of the normal physiology of BEC and the pathogenic consequences of reduced AE2 expression, including abnormal intrinsic characteristics of BEC and their production of signal molecules that lead to the chronic inflammatory responses in small bile ducts.
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U2 - 10.1016/j.jaut.2016.08.006
DO - 10.1016/j.jaut.2016.08.006
M3 - Article
C2 - 27592379
AN - SCOPUS:84995579603
VL - 75
SP - 150
EP - 160
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
ER -