title: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Hui
authors.forename: Eagle S H
authors.initials: ES
authors.lastname: Chu
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
authors.forename: Minnie Y Y
authors.initials: MY
authors.lastname: Go
authors.forename: Henry L Y
authors.initials: HL
authors.lastname: Chan
authors.forename: Wai K
authors.initials: WK
authors.lastname: Leung
authors.forename: Kin F
authors.initials: KF
authors.lastname: Cheung
authors.forename: Arthur K K
authors.initials: AK
authors.lastname: Ching
authors.forename: Yiu L
authors.initials: YL
authors.lastname: Chui
authors.forename: Ka K
authors.initials: KK
authors.lastname: Chan
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
mesh_terms: D000818:Animals; D017209:Apoptosis; D000068579:Celecoxib; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006133:Growth Substances / Q000378:metabolism; D006520:Hepatitis, Animal / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D022781:Hepatocytes / Q000201:enzymology; D007124:Immunoenzyme Techniques; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008214:Lymphocytes / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use
chemical_list: D018925:Chemokines; D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D006133:Growth Substances; D016328:NF-kappa B; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone