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Article: Expression of a cyclo-oxygenase-2 transgene in murine liver causes hepatitis
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TitleExpression of a cyclo-oxygenase-2 transgene in murine liver causes hepatitis
 
AuthorsYu, J2
Hui, AY2
Chu, ESH2
Cheng, ASL2
Go, MYY2
Chan, HLY2
Leung, WK2
Cheung, KF2
Ching, AKK2
Chui, YL2
Chan, KK2
Sung, JJY1 2
 
Issue Date2007
 
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
 
CitationGut, 2007, v. 56 n. 7, p. 991-999 [How to Cite?]
DOI: http://dx.doi.org/10.1136/gut.2006.097923
 
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.
 
ISSN0017-5749
2013 Impact Factor: 13.319
 
DOIhttp://dx.doi.org/10.1136/gut.2006.097923
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorYu, J
 
dc.contributor.authorHui, AY
 
dc.contributor.authorChu, ESH
 
dc.contributor.authorCheng, ASL
 
dc.contributor.authorGo, MYY
 
dc.contributor.authorChan, HLY
 
dc.contributor.authorLeung, WK
 
dc.contributor.authorCheung, KF
 
dc.contributor.authorChing, AKK
 
dc.contributor.authorChui, YL
 
dc.contributor.authorChan, KK
 
dc.contributor.authorSung, JJY
 
dc.date.accessioned2012-09-05T05:27:27Z
 
dc.date.available2012-09-05T05:27:27Z
 
dc.date.issued2007
 
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.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationGut, 2007, v. 56 n. 7, p. 991-999 [How to Cite?]
DOI: http://dx.doi.org/10.1136/gut.2006.097923
 
dc.identifier.citeulike1451739
 
dc.identifier.doihttp://dx.doi.org/10.1136/gut.2006.097923
 
dc.identifier.epage999
 
dc.identifier.issn0017-5749
2013 Impact Factor: 13.319
 
dc.identifier.issue7
 
dc.identifier.pmid17148503
 
dc.identifier.scopuseid_2-s2.0-34347224048
 
dc.identifier.spage991
 
dc.identifier.urihttp://hdl.handle.net/10722/163089
 
dc.identifier.volume56
 
dc.languageeng
 
dc.publisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofGut
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAnimals
 
dc.subject.meshApoptosis
 
dc.subject.meshCell Proliferation
 
dc.subject.meshChemokines - Metabolism
 
dc.subject.meshChemotaxis
 
dc.subject.meshCyclooxygenase 2 - Genetics - Metabolism - Physiology
 
dc.subject.meshCyclooxygenase 2 Inhibitors - Therapeutic Use
 
dc.subject.meshCytokines - Metabolism
 
dc.subject.meshDinoprostone - Metabolism
 
dc.subject.meshFemale
 
dc.subject.meshGene Expression
 
dc.subject.meshGrowth Substances - Metabolism
 
dc.subject.meshHepatitis, Animal - Drug Therapy - Enzymology - Pathology
 
dc.subject.meshHepatocytes - Enzymology
 
dc.subject.meshImmunoenzyme Techniques
 
dc.subject.meshLiver - Enzymology - Pathology
 
dc.subject.meshLymphocytes - Physiology
 
dc.subject.meshMacrophages - Physiology
 
dc.subject.meshMice
 
dc.subject.meshMice, Transgenic
 
dc.subject.meshNf-Kappa B - Metabolism
 
dc.subject.meshPyrazoles - Therapeutic Use
 
dc.subject.meshSulfonamides - Therapeutic Use
 
dc.titleExpression of a cyclo-oxygenase-2 transgene in murine liver causes hepatitis
 
dc.typeArticle
 
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<item><contributor.author>Yu, J</contributor.author>
<contributor.author>Hui, AY</contributor.author>
<contributor.author>Chu, ESH</contributor.author>
<contributor.author>Cheng, ASL</contributor.author>
<contributor.author>Go, MYY</contributor.author>
<contributor.author>Chan, HLY</contributor.author>
<contributor.author>Leung, WK</contributor.author>
<contributor.author>Cheung, KF</contributor.author>
<contributor.author>Ching, AKK</contributor.author>
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<description.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-&#954;B) 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-&#954;B and inflammatory cytokine cascade, with a marked expression of the proinflammatory cytokines tumour necrosis factor (TNF)-&#945; (9.4-fold), interleukin (IL)-6 (4.4-fold), IL-1&#946; (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-&#954;B, stimulating the secretion of proinflammatory cytokines, recruiting macrophage and altering cell kinetics. Inhibition of COX-2 represents a mechanism-based chemopreventive approach to hepatitis.</description.abstract>
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Author Affiliations
  1. Prince of Wales Hospital Hong Kong
  2. Chinese University of Hong Kong