TITLE

Expression of a cyclo-oxygenase-2 transgene in murine liver causes hepatitis

AUTHOR(S)
Yu, Jun; Hui, Alex Y.; Chu, Eagle S. H.; Cheng, Alfred S. L.; Go, Minnie Y. Y.; Chan, Henry L. Y.; Leung, Wai K.; Cheung, Kin F.; Ching, Arthur K. K.; Chui, Yiu L.; Chan, Ka K.; Sung, Joseph J. Y.
PUB. DATE
July 2007
SOURCE
Gut;Jul2007, Vol. 56 Issue 7, p991
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: It has been proved that cyclo-oxygenase-2 (COX-2) is rapidly induced by inflammatory mediators. However, it is not known whether overexpression of COX-2 in the liver is sufficient to promote activation or secretion of inflammatory factors leading to hepatitis. Aim: To investigate the role forced expression of COX-2 in liver by using inducible COX-2 transgenic (TG) mice. Methods: TG mice that overexpress the human COX-2 gene in the liver using the liver-specific transthyretin promoter and non-TG littermates were derived and fed the normal diet far up to 12 months. Hepatic prostaglandin E2 (PGE2) content was determined using enzyme immunoassay, nuclear factor kappaB (NF-KB) activation by electrophoretic mobilily shift assays, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labelling and proliferation by Ki-67 immunohistochemistry. Results: COX-2 TG mice exhibited strongly increased COX-2 and PGE2, elevated serum alanine aminotransferase level and histological hepatitis. Hepatic COX-2 expression in the TG mice resulted in activation of NF-κB and inflammatory cytokine cascade, with a marked expression of the proinflammatory cytokines tumour necrosis factor (TNF)-α (9.4-fald), interleukin (IL)-6 (4.4-fold), IL-1β (3.6-fold), and of the anti-inflammatory cytokine IL-10 (4.4-fald) and chemokine macrophage inflammatory protein-2 (3.2-fald). The inflammatory response of the COX-2 TG mice was associated with infiltration macrophages and lymphocytes, increased cell proliferation and high rates of cell apoptosis. Administration of the COX-2 inhibitor celecoxib in TG mice restored liver histology to normal. Conclusion: Enhanced COX-2 expression in hepatocytes is sufficient to induce hepatitis by activating NF-κB, stimulating the secretion of proinflammatory cytokines, recruiting macrophage and altering cell kinetics. Inhibition of COX-2 represents a mechanism-based chemopreventive approach to hepatitis.
ACCESSION #
25602408

 

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