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

TitleExpression of a cyclo-oxygenase-2 transgene in murine liver causes hepatitis
Authors
Issue Date2007
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
Citation
Gut, 2007, v. 56 n. 7, p. 991-999 How to Cite?
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-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 PGE 2, 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.
Persistent Identifierhttp://hdl.handle.net/10722/163089
ISSN
2013 Impact Factor: 13.319
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYu, Jen_US
dc.contributor.authorHui, AYen_US
dc.contributor.authorChu, ESHen_US
dc.contributor.authorCheng, ASLen_US
dc.contributor.authorGo, MYYen_US
dc.contributor.authorChan, HLYen_US
dc.contributor.authorLeung, WKen_US
dc.contributor.authorCheung, KFen_US
dc.contributor.authorChing, AKKen_US
dc.contributor.authorChui, YLen_US
dc.contributor.authorChan, KKen_US
dc.contributor.authorSung, JJYen_US
dc.date.accessioned2012-09-05T05:27:27Z-
dc.date.available2012-09-05T05:27:27Z-
dc.date.issued2007en_US
dc.identifier.citationGut, 2007, v. 56 n. 7, p. 991-999en_US
dc.identifier.issn0017-5749en_US
dc.identifier.urihttp://hdl.handle.net/10722/163089-
dc.description.abstractBackground: 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-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 PGE 2, 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.en_US
dc.languageengen_US
dc.publisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/en_US
dc.relation.ispartofGuten_US
dc.subject.meshAnimalsen_US
dc.subject.meshApoptosisen_US
dc.subject.meshCell Proliferationen_US
dc.subject.meshChemokines - Metabolismen_US
dc.subject.meshChemotaxisen_US
dc.subject.meshCyclooxygenase 2 - Genetics - Metabolism - Physiologyen_US
dc.subject.meshCyclooxygenase 2 Inhibitors - Therapeutic Useen_US
dc.subject.meshCytokines - Metabolismen_US
dc.subject.meshDinoprostone - Metabolismen_US
dc.subject.meshFemaleen_US
dc.subject.meshGene Expressionen_US
dc.subject.meshGrowth Substances - Metabolismen_US
dc.subject.meshHepatitis, Animal - Drug Therapy - Enzymology - Pathologyen_US
dc.subject.meshHepatocytes - Enzymologyen_US
dc.subject.meshImmunoenzyme Techniquesen_US
dc.subject.meshLiver - Enzymology - Pathologyen_US
dc.subject.meshLymphocytes - Physiologyen_US
dc.subject.meshMacrophages - Physiologyen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Transgenicen_US
dc.subject.meshNf-Kappa B - Metabolismen_US
dc.subject.meshPyrazoles - Therapeutic Useen_US
dc.subject.meshSulfonamides - Therapeutic Useen_US
dc.titleExpression of a cyclo-oxygenase-2 transgene in murine liver causes hepatitisen_US
dc.typeArticleen_US
dc.identifier.emailLeung, WK:waikleung@hku.hken_US
dc.identifier.authorityLeung, WK=rp01479en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1136/gut.2006.097923en_US
dc.identifier.pmid17148503en_US
dc.identifier.scopuseid_2-s2.0-34347224048en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-34347224048&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume56en_US
dc.identifier.issue7en_US
dc.identifier.spage991en_US
dc.identifier.epage999en_US
dc.identifier.isiWOS:000247205000019-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridYu, J=35351306800en_US
dc.identifier.scopusauthoridHui, AY=7102453670en_US
dc.identifier.scopusauthoridChu, ESH=8631130300en_US
dc.identifier.scopusauthoridCheng, ASL=7402075036en_US
dc.identifier.scopusauthoridGo, MYY=7101882939en_US
dc.identifier.scopusauthoridChan, HLY=16038785900en_US
dc.identifier.scopusauthoridLeung, WK=7201504523en_US
dc.identifier.scopusauthoridCheung, KF=7402406701en_US
dc.identifier.scopusauthoridChing, AKK=35083263600en_US
dc.identifier.scopusauthoridChui, YL=7004982375en_US
dc.identifier.scopusauthoridChan, KK=8599737700en_US
dc.identifier.scopusauthoridSung, JJY=35405352400en_US
dc.identifier.citeulike1451739-

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