Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis

Thucydides L. Salunga, Zheng Guo Cui, Shinji Shimoda, Hua Chuan Zheng, Kazuhiro Nomoto, Takashi Kondo, Yasuo Takano, Carlo Selmi, Gianfranco Alpini, M. Eric Gershwin, Koichi Tsuneyama

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

There has been a relative paucity of effort at defining effector mechanisms of biliary damage in PBC. We hypothesize that biliary cells are destroyed secondary to the immunologic relationships of inflammation and biliary epithelial apoptosis and, in particular, that biliary damage is a result of reduced levels of glutathione-S-transferase (GST), the production of hypochlorous acid (HOCl) and its association with eosinophil peroxidase (EPO). To address this issue, we examined the expression of EPO and GST in PBC and control livers and demonstrated an increase of EPO within the portal areas of PBC. We also demonstrated that macrophages have evidence of phagocytosed EPO. Furthermore, we studied the influence of HOCl on apoptosis in cultured human biliary epithelial cells (BEC) as well as the associated activity of Bcl-2, Bax, p-JNK, JNK, p53, Fas and caspase-3. HOC1-induced apoptosis in BEC in a dose-dependent fashion increased the activity of caspase-3 and the expression of p53 and p-JNK. Pretreatment with l-buthionine-(S,R)-sulfoximine, a glutathione (GSH) inhibitor, potentiated the sensitivity of BEC to HOCl-induced apoptosis. We conclude that intracellular GSH reduction leads directly to BEC apoptosis. Modulation of these events will be critical to reduce immune-mediated destruction.

Original languageEnglish (US)
Pages (from-to)78-86
Number of pages9
JournalJournal of Autoimmunity
Volume29
Issue number2-3
DOIs
StatePublished - Sep 2007
Externally publishedYes

Fingerprint

Eosinophil Peroxidase
Biliary Liver Cirrhosis
Bile Ducts
Oxidative Stress
Hypochlorous Acid
Apoptosis
Epithelial Cells
Glutathione Transferase
Caspase 3
Glutathione
Phagocytosis
Macrophages
Inflammation
Liver

Keywords

  • Apoptosis
  • Autoimmunity
  • Biliary epithelial cells
  • Cholangiocytes
  • Oxidation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Salunga, T. L., Cui, Z. G., Shimoda, S., Zheng, H. C., Nomoto, K., Kondo, T., ... Tsuneyama, K. (2007). Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis. Journal of Autoimmunity, 29(2-3), 78-86. https://doi.org/10.1016/j.jaut.2007.04.002

Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis. / Salunga, Thucydides L.; Cui, Zheng Guo; Shimoda, Shinji; Zheng, Hua Chuan; Nomoto, Kazuhiro; Kondo, Takashi; Takano, Yasuo; Selmi, Carlo; Alpini, Gianfranco; Gershwin, M. Eric; Tsuneyama, Koichi.

In: Journal of Autoimmunity, Vol. 29, No. 2-3, 09.2007, p. 78-86.

Research output: Contribution to journalArticle

Salunga, TL, Cui, ZG, Shimoda, S, Zheng, HC, Nomoto, K, Kondo, T, Takano, Y, Selmi, C, Alpini, G, Gershwin, ME & Tsuneyama, K 2007, 'Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis', Journal of Autoimmunity, vol. 29, no. 2-3, pp. 78-86. https://doi.org/10.1016/j.jaut.2007.04.002
Salunga, Thucydides L. ; Cui, Zheng Guo ; Shimoda, Shinji ; Zheng, Hua Chuan ; Nomoto, Kazuhiro ; Kondo, Takashi ; Takano, Yasuo ; Selmi, Carlo ; Alpini, Gianfranco ; Gershwin, M. Eric ; Tsuneyama, Koichi. / Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis. In: Journal of Autoimmunity. 2007 ; Vol. 29, No. 2-3. pp. 78-86.
@article{333cb5a071064b0990c02c504658203d,
title = "Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis",
abstract = "There has been a relative paucity of effort at defining effector mechanisms of biliary damage in PBC. We hypothesize that biliary cells are destroyed secondary to the immunologic relationships of inflammation and biliary epithelial apoptosis and, in particular, that biliary damage is a result of reduced levels of glutathione-S-transferase (GST), the production of hypochlorous acid (HOCl) and its association with eosinophil peroxidase (EPO). To address this issue, we examined the expression of EPO and GST in PBC and control livers and demonstrated an increase of EPO within the portal areas of PBC. We also demonstrated that macrophages have evidence of phagocytosed EPO. Furthermore, we studied the influence of HOCl on apoptosis in cultured human biliary epithelial cells (BEC) as well as the associated activity of Bcl-2, Bax, p-JNK, JNK, p53, Fas and caspase-3. HOC1-induced apoptosis in BEC in a dose-dependent fashion increased the activity of caspase-3 and the expression of p53 and p-JNK. Pretreatment with l-buthionine-(S,R)-sulfoximine, a glutathione (GSH) inhibitor, potentiated the sensitivity of BEC to HOCl-induced apoptosis. We conclude that intracellular GSH reduction leads directly to BEC apoptosis. Modulation of these events will be critical to reduce immune-mediated destruction.",
keywords = "Apoptosis, Autoimmunity, Biliary epithelial cells, Cholangiocytes, Oxidation",
author = "Salunga, {Thucydides L.} and Cui, {Zheng Guo} and Shinji Shimoda and Zheng, {Hua Chuan} and Kazuhiro Nomoto and Takashi Kondo and Yasuo Takano and Carlo Selmi and Gianfranco Alpini and Gershwin, {M. Eric} and Koichi Tsuneyama",
year = "2007",
month = "9",
doi = "10.1016/j.jaut.2007.04.002",
language = "English (US)",
volume = "29",
pages = "78--86",
journal = "Journal of Autoimmunity",
issn = "0896-8411",
publisher = "Academic Press Inc.",
number = "2-3",

}

TY - JOUR

T1 - Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis

AU - Salunga, Thucydides L.

AU - Cui, Zheng Guo

AU - Shimoda, Shinji

AU - Zheng, Hua Chuan

AU - Nomoto, Kazuhiro

AU - Kondo, Takashi

AU - Takano, Yasuo

AU - Selmi, Carlo

AU - Alpini, Gianfranco

AU - Gershwin, M. Eric

AU - Tsuneyama, Koichi

PY - 2007/9

Y1 - 2007/9

N2 - There has been a relative paucity of effort at defining effector mechanisms of biliary damage in PBC. We hypothesize that biliary cells are destroyed secondary to the immunologic relationships of inflammation and biliary epithelial apoptosis and, in particular, that biliary damage is a result of reduced levels of glutathione-S-transferase (GST), the production of hypochlorous acid (HOCl) and its association with eosinophil peroxidase (EPO). To address this issue, we examined the expression of EPO and GST in PBC and control livers and demonstrated an increase of EPO within the portal areas of PBC. We also demonstrated that macrophages have evidence of phagocytosed EPO. Furthermore, we studied the influence of HOCl on apoptosis in cultured human biliary epithelial cells (BEC) as well as the associated activity of Bcl-2, Bax, p-JNK, JNK, p53, Fas and caspase-3. HOC1-induced apoptosis in BEC in a dose-dependent fashion increased the activity of caspase-3 and the expression of p53 and p-JNK. Pretreatment with l-buthionine-(S,R)-sulfoximine, a glutathione (GSH) inhibitor, potentiated the sensitivity of BEC to HOCl-induced apoptosis. We conclude that intracellular GSH reduction leads directly to BEC apoptosis. Modulation of these events will be critical to reduce immune-mediated destruction.

AB - There has been a relative paucity of effort at defining effector mechanisms of biliary damage in PBC. We hypothesize that biliary cells are destroyed secondary to the immunologic relationships of inflammation and biliary epithelial apoptosis and, in particular, that biliary damage is a result of reduced levels of glutathione-S-transferase (GST), the production of hypochlorous acid (HOCl) and its association with eosinophil peroxidase (EPO). To address this issue, we examined the expression of EPO and GST in PBC and control livers and demonstrated an increase of EPO within the portal areas of PBC. We also demonstrated that macrophages have evidence of phagocytosed EPO. Furthermore, we studied the influence of HOCl on apoptosis in cultured human biliary epithelial cells (BEC) as well as the associated activity of Bcl-2, Bax, p-JNK, JNK, p53, Fas and caspase-3. HOC1-induced apoptosis in BEC in a dose-dependent fashion increased the activity of caspase-3 and the expression of p53 and p-JNK. Pretreatment with l-buthionine-(S,R)-sulfoximine, a glutathione (GSH) inhibitor, potentiated the sensitivity of BEC to HOCl-induced apoptosis. We conclude that intracellular GSH reduction leads directly to BEC apoptosis. Modulation of these events will be critical to reduce immune-mediated destruction.

KW - Apoptosis

KW - Autoimmunity

KW - Biliary epithelial cells

KW - Cholangiocytes

KW - Oxidation

UR - http://www.scopus.com/inward/record.url?scp=34548527467&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548527467&partnerID=8YFLogxK

U2 - 10.1016/j.jaut.2007.04.002

DO - 10.1016/j.jaut.2007.04.002

M3 - Article

VL - 29

SP - 78

EP - 86

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

SN - 0896-8411

IS - 2-3

ER -