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


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 E2 (PGE2) content was determined using enzyme immunoassay, nuclear factor kappaB (NF-κB) 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 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-fold), interleukin (IL)-6 (4.4-fold), IL-1β (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-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.

  • ALT, alanine aminotransferase
  • cDNA, complementary DNA
  • COX, cyclo-oxygenase
  • IL, interleukin
  • IP-10, interferon-γ-inducible protein-10
  • MIP-2, macrophage inflammatory protein-2
  • NF-κB, nuclear factor-kappaB
  • PI, proliferation index
  • PGE2, prostaglandin E2
  • TG, transgenic
  • TGF-β1, transforming growth factor-β1
  • TNF-α, tumour necrosis factor-α
  • TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labelling
  • WT, wild type

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