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Expression of a cyclo-oxygenase-2 transgene in murine liver causes hepatitis
  1. Jun Yu1,
  2. Alex Y Hui1,
  3. Eagle S H Chu1,
  4. Alfred S L Cheng1,
  5. Minnie Y Y Go1,
  6. Henry L Y Chan1,
  7. Wai K Leung1,
  8. Kin F Cheung1,
  9. Arthur K K Ching2,
  10. Yiu L Chui2,
  11. Ka K Chan1,
  12. Joseph J Y Sung1
  1. 1Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
  2. 2Clinical Immunology Unit, The Chinese University of Hong Kong, Hong Kong, China
  1. Correspondence to:
    Professor J J Y Sung
    Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong; joesung{at}cuhk.edu.hk

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 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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Footnotes

  • Published Online First 4 December 2006

  • Financial support: This project was funded by a Research Grants Council Competitive Earmarked Research Grant, CUHK4446/03M, and the Clinical Research Fellowship Scheme (AYH) jointly sponsored by Research Grants Council and the Chinese University of Hong Kong, Hong Kong.

  • Competing interests: None.

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