Basic Research
Copyright ©2007 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 21, 2007; 13(47): 6379-6384
Published online Dec 21, 2007. doi: 10.3748/wjg.v13.i47.6379
Inflammatory cytokines promote inducible nitric oxide synthase-mediated DNA damage in hamster gallbladder epithelial cells
Amane Kitasato, Yoshitsugu Tajima, Tamotsu Kuroki, Ryuji Tsutsumi, Tomohiko Adachi, Takehiro Mishima, Takashi Kanematsu
Amane Kitasato, Yoshitsugu Tajima, Tamotsu Kuroki, Ryuji Tsutsumi, Tomohiko Adachi, Takehiro Mishima, Takashi Kanematsu, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
Author contributions: All authors contributed equally to the work.
Correspondence to: Amane Kitasato, MD, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. a-kit@bg8.so-net.ne.jp
Telephone: + 81-958-497316 Fax: + 81-958-497319
Received: January 4, 2007
Revised: September 8, 2007
Accepted: November 17, 2007
Published online: December 21, 2007
Abstract

AIM: To investigate the link between chronic biliary inflammation and carcinogenesis using hamster gallbladder epithelial cells.

METHODS: Gallbladder epithelial cells were isolated from hamsters and cultured with a mixture of inflammatory cytokines including interleukin-1β, interferon-γ, and tumor necrosis factor-α. Inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) generation, and DNA damage were evaluated.

RESULTS: NO generation was increased significantly following cytokine stimulation, and suppressed by an iNOS inhibitor. iNOS mRNA expression was demonstrated in the gallbladder epithelial cells during exposure to inflammatory cytokines. Furthermore, NO-dependent DNA damage, estimated by the comet assay, was significantly increased by cytokines, and decreased to control levels by an iNOS inhibitor.

CONCLUSION: Cytokine stimulation induced iNOS expression and NO generation in normal hamster gallbladder epithelial cells, which was sufficient to cause DNA damage. These results indicate that NO-mediated genotoxicity induced by inflammatory cytokines through activation of iNOS may be involved in the process of biliary carcinogenesis in response to chronic inflammation of the biliary tree.

Keywords: Biliary carcinoma, Inflammation, Inflammatory cytokine, Nitric oxide, Inducible nitric oxide synthase, DNA damage, Gallbladder epithelial cell, Hamster