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.
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.
Authors: K Seibert; Y Zhang; K Leahy; S Hauser; J Masferrer; W Perkins; L Lee; P Isakson Journal: Proc Natl Acad Sci U S A Date: 1994-12-06 Impact factor: 11.205
Authors: Soung Won Jeong; Jae Young Jang; Sae Hwan Lee; Sang Gyun Kim; Young Koog Cheon; Young Seok Kim; Young Deok Cho; Hong Soo Kim; Joon Seong Lee; So-Young Jin; Chan Sup Shim; Boo Sung Kim Journal: Korean J Intern Med Date: 2010-11-27 Impact factor: 2.884
Authors: Alexandra T Gruia; Lucian Barbu-Tudoran; Ani A Mic; Valentin L Ordodi; Virgil Paunescu; Felix A Mic Journal: Histochem Cell Biol Date: 2011-05-29 Impact factor: 4.304