Ethanol and Arachidonic Acid Synergize to Activate Kupffer Cells and Modulate the Fibrogenic Response via Tumor Necrosis Factor , Reduced Glutathione, and Transforming Growth Factor beta–Dependent Mechanisms

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dc.contributor.authorCubero Palero, Francisco Javier
dc.contributor.authorNieto, Natalia
dc.date.accessioned2024-02-01T12:28:41Z
dc.date.available2024-02-01T12:28:41Z
dc.date.issued2008-08-04
dc.descriptionAbbreviations: alpha-SMA, alpha-smooth muscle actin; AA, arachidonic acid; DPI, diphenyleneiodonium; ECM, extracellular matrix; GSH, reduced glutathione; GSSG, oxidized glutathione; HSC, hepatic stellate cells; HSCcontrol, control stellate cells; HSCethanol, stellate cells from ethanol-fed rats; KC, Kupffer cells; KCcontrol, control Kupffer cells; KCethanol, Kupffer cells from ethanol-fed rats; PUFA, polyunsaturated fatty acids; NADPH, nicotinamide adenine dinucleotide phosphate reduced form; ROS, reactive oxygen species; SEM, standard error of the mean; TGF- , transforming growth factor beta; TNF- , tumor necrosis factor alpha. From the Department of Medicine, Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY. Both authors contributed equally to the experimental part of this work Received June 7, 2008; accepted August 4, 2008. Supported by a Postdoctoral Fellowship from the Spanish Ministry of Education and Science Ref. No. EX2006-0070 (F.J.C) and by the US Public Health Service Grant 5R01DK069286-03 from the National Institute of Diabetes and Digestive and Kidney Diseases (N.N.). Address reprint requests to: Natalia Nieto, Department of Medicine, Division of Liver Diseases, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029. E-mail: natalia.nieto@mssm.edu; fax: 212-849-2574. Copyright © 2008 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.22592 Potential conflict of interest: Nothing to report. Additional Supporting Information may be found in the online version of this article.
dc.description.abstractBecause of the contribution of ethanol and polyunsaturated fatty acids (PUFAs) to alcoholic liver disease, we investigated whether chronic ethanol administration and arachidonic acid (AA) could synergistically mediate Kupffer cell (KC) activation and modulate the stellate cell (HSC) fibrogenic response. Results: (1) the effects of ethanol and AA on KC and HSC were as follows: Cell proliferation, lipid peroxidation, H(2)O(2), O(2).(-), nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase activity, and tumor necrosis factor alpha (TNF-alpha) were higher in KC(ethanol) than in KC(control), and were enhanced by AA; HSC(ethanol) proliferated faster, increased collagen, and showed higher GSH than HSC(control), with modest effects by AA. (2) AA effects on the control co-culture: We previously reported the ability of KC to induce a pro-fibrogenic response in HSC via reactive oxygen species (ROS)-dependent mechanisms; we now show that AA further increases cell proliferation and collagen in the control co-culture. The latter was prevented by vitamin E (an antioxidant) and by diphenyleneiodonium (a NADPH oxidase inhibitor). (3) Ethanol effects on the co-cultures: Co-culture with KC(control) or KC(ethanol) induced HSC(control) and HSC(ethanol) proliferation; however, the pro-fibrogenic response in HSC(ethanol) was suppressed because of up-regulation of TNF-alpha and GSH, which was prevented by a TNF-alpha neutralizing antibody (Ab) and by L-buthionine-sulfoximine, a GSH-depleting agent. (4) Ethanol plus AA effects on the co-cultures: AA lowered TNF-alpha in the HSC(control) co-cultures, allowing for enhanced collagen deposition; furthermore, AA restored the pro-fibrogenic response in the HSC(ethanol) co-cultures by counteracting the up-regulation of TNF-alpha and GSH with a significant increase in GSSG and in pro-fibrogenic transforming growth factor beta (TGF-beta). Conclusion: These results unveil synergism between ethanol and AA to the mechanism whereby KC mediate ECM remodeling and suggest that even if chronic ethanol consumption sensitizes HSC to up-regulate anti-fibrogenic signals, their effects are blunted by a second "hit" such as AA.
dc.description.departmentDepto. de Inmunología, Oftalmología y ORL
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.statuspub
dc.identifier.citationCubero FJ, Nieto N. Ethanol and arachidonic acid synergize to activate Kupffer cells and modulate the fibrogenic response via tumor necrosis factor alpha, reduced glutathione, and transforming growth factor beta-dependent mechanisms. Hepatology. 2008 Dec;48(6):2027-2039. doi: 10.1002/hep.22592. PMID: 19003881; PMCID: PMC4477289.
dc.identifier.doi10.1002/hep.22592
dc.identifier.issn0270-9139
dc.identifier.officialurlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477289/pdf/nihms-77261.pdf
dc.identifier.pmid19003881
dc.identifier.relatedurlhttps://pubmed.ncbi.nlm.nih.gov/19003881/
dc.identifier.urihttps://hdl.handle.net/20.500.14352/97673
dc.issue.number6
dc.journal.titleHepatology.
dc.language.isoeng
dc.page.final2039
dc.page.initial2027
dc.publisherLippincott, Williams & Wilkins
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.cdu577
dc.subject.ucmCiencias Biomédicas
dc.subject.ucmBiología
dc.subject.ucmBiología celular (Biología)
dc.subject.ucmBiología molecular (Biología)
dc.subject.ucmInmunología
dc.subject.unesco24 Ciencias de la Vida
dc.subject.unesco2407 Biología Celular
dc.subject.unesco2412 Inmunología
dc.subject.unesco2415 Biología Molecular
dc.titleEthanol and Arachidonic Acid Synergize to Activate Kupffer Cells and Modulate the Fibrogenic Response via Tumor Necrosis Factor , Reduced Glutathione, and Transforming Growth Factor beta–Dependent Mechanisms
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number48
dspace.entity.typePublication
relation.isAuthorOfPublicationb3877679-0fbd-42e6-8541-1efeb2df768a
relation.isAuthorOfPublication.latestForDiscoveryb3877679-0fbd-42e6-8541-1efeb2df768a
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