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

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 for up to 12 months. Hepatic prostaglandin E(2) (PGE(2)) content was determined using enzyme immunoassay, nuclear factor kappaB (NF-kappaB) activation by electrophoretic mobility 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 PGE(2), elevated serum alanine aminotransferase level and histological hepatitis. Hepatic COX-2 expression in the TG mice resulted in activation of NF-kappaB and inflammatory cytokine cascade, with a marked expression of the proinflammatory cytokines tumour necrosis factor (TNF)-alpha (9.4-fold), interleukin (IL)-6 (4.4-fold), IL-1beta (3.6-fold), and of the anti-inflammatory cytokine IL-10 (4.4-fold) and chemokine macrophage inflammatory protein-2 (3.2-fold). 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-kappaB, stimulating the secretion of proinflammatory cytokines, recruiting macrophage and altering cell kinetics. Inhibition of COX-2 represents a mechanism-based chemopreventive approach to hepatitis.

SUBMITTER: Yu J

PROVIDER: S-EPMC1994375 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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

Yu Jun J Hui Alex Y AY Chu Eagle S H ES Cheng Alfred S L AS Go Minnie Y Y MY Chan Henry L Y HL Leung Wai K WK Cheung Kin F KF Ching Arthur K K AK Chui Yiu L YL Chan Ka K KK Sung Joseph J Y JJ

Gut 20061205 7

<h4>Background</h4>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.<h4>Aim</h4>To investigate the role forced expression of COX-2 in liver by using inducible COX-2 transgenic (TG) mice.<h4>Methods</h4>TG mice that overexpress the human COX-2 gene in the liver using the liver-specific tra ...[more]

PMID: 17148503

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Dataset Information

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

Publications

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

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