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

63 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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  • Cite this

    Salunga, T. L., Cui, Z. G., Shimoda, S., Zheng, H. C., Nomoto, K., Kondo, T., Takano, Y., Selmi, C., Alpini, G., Gershwin, M. E., & 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