Hydrophobic bile acids suppress expression of AE2 in biliary epithelial cells and induce bile duct inflammation in primary biliary cholangitis.
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.
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: hisamoto@intmed1.med.kyushu-u.ac.jp.
Satomi
S
Hisamoto
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: sshimoda@intmed1.med.kyushu-u.ac.jp.
Shinji
S
Shimoda
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan. Electronic address: kenichih@med.kanazawa-u.ac.jp.
Kenichi
K
Harada
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: make_my_own_niche@yahoo.co.jp.
Sho
S
Iwasaka
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: onohara.shinya.678@m.kyushu-u.ac.jp.
Shinya
S
Onohara
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: cychong@gj9.so-net.ne.jp.
Yong
Y
Chong
Clinical Research Center in National Hospital Organization (NHO), Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan. Electronic address: nakamuram@nagasaki-mc.com.
Minoru
M
Nakamura
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: y-bekki@med.kyushu-u.ac.jp.
Yuki
Y
Bekki
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: yosizumi@surg2.med.kyushu-u.ac.jp.
Tomoharu
T
Yoshizumi
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: tikesurg@surg2.med.kyushu-u.ac.jp.
Toru
T
Ikegami
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: maehara@surg2.med.kyushu-u.ac.jp.
Yoshihiko
Y
Maehara
Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California at Davis, Davis, CA, USA. Electronic address: xiaosong@stanford.edu.
Xiao-Song
XS
He
Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California at Davis, Davis, CA, USA. Electronic address: megershwin@ucdavis.edu.
M Eric
ME
Gershwin
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: akashi@med.kyushu-u.ac.jp.
Koichi
K
Akashi
D001647:Bile Acids and Salts / Q000737:chemistry / Q000494:pharmacology*; D001652:Bile Ducts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001659:Biliary Tract / Q000378:metabolism / Q000473:pathology; D019013:CD40 Antigens / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D027963:Chloride-Bicarbonate Antiporters / Q000235:genetics* / Q000378:metabolism; D002761:Cholangitis / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001647:Bile Acids and Salts; D019013:CD40 Antigens; D018925:Chemokines; D027963:Chloride-Bicarbonate Antiporters; D016207:Cytokines; D006684:HLA-DR Antigens; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species
Autoimmune cholangitis; Cholangiocytes; Cytokine; Inflammation