Inhibition of RelA-Ser536 phosphorylation by a competing peptide reduces mouse liver fibrosis without blocking the innate immune response

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dc.contributor.authorMoles, A.
dc.contributor.authorSanchez, A.
dc.contributor.authorBanks, P.
dc.contributor.authorMurphy, L.
dc.contributor.authorLuli, S.
dc.contributor.authorBorthwick, L.
dc.contributor.authorFisher, A.
dc.contributor.authorO'Reilly, S.
dc.contributor.authorvan Laar, J.
dc.contributor.authorWhite, S.
dc.contributor.authorPerkins, N.
dc.contributor.authorBurt, A.
dc.contributor.authorMann, D.
dc.contributor.authorOakley, F.
dc.date.issued2013
dc.description.abstractPhosphorylation of the RelA subunit at serine 536 (RelA-P-Ser536) is important for hepatic myofibroblast survival and is mechanistically implicated in liver fibrosis. Here, we show that a cell-permeable competing peptide (P6) functions as a specific targeted inhibitor of RelA-P-Ser536 in vivo and exerts an antifibrogenic effect in two progressive liver disease models, but does not impair hepatic inflammation or innate immune responses after lipopolysaccharide challenge. Using kinase assays and western blotting, we confirm that P6 is a substrate for the inhibitory kappa B kinases (IKKs), IKKα and IKKβ, and, in human hepatic myofibroblasts, P6 prevents RelA-P-Ser536, but does not affect IKK activation of IκBα. We demonstrate that RelA-P-Ser536 is a feature of human lung and skin fibroblasts, but not lung epithelial cells, in vitro and is present in sclerotic skin and diseased lungs of patients suffering from idiopathic pulmonary fibrosis. Conclusion: RelA-P-Ser536 may be a core fibrogenic regulator of fibroblast phenotype.
dc.description.statementofresponsibilityAnna Moles, Ana M. Sanchez, Paul S. Banks, Lindsay B. Murphy, Saimir Luli, Lee Borthwick, Andrew Fisher, Steven O'Reilly, Jacob M. van Laar, Steven A. White, Neil D. Perkins, Alastair D. Burt, Derek A. Mann and Fiona Oakley
dc.identifier.citationHepatology, 2013; 57(2):817-828
dc.identifier.doi10.1002/hep.26068
dc.identifier.issn0270-9139
dc.identifier.issn1527-3350
dc.identifier.orcidBurt, A. [0000-0002-3011-7774]
dc.identifier.urihttp://hdl.handle.net/2440/85688
dc.language.isoen
dc.publisherJohn Wiley & Sons
dc.rights© 2012 American Association for the Study of Liver Diseases
dc.source.urihttps://doi.org/10.1002/hep.26068
dc.subjectFibroblasts
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectLiver Cirrhosis
dc.subjectCarbon Tetrachloride Poisoning
dc.subjectLipopolysaccharides
dc.subjectSerine
dc.subjectPeptide Fragments
dc.subjectPhosphorylation
dc.subjectAdult
dc.subjectMale
dc.subjectI-kappa B Kinase
dc.subjectTranscription Factor RelA
dc.subjectImmunity, Innate
dc.titleInhibition of RelA-Ser536 phosphorylation by a competing peptide reduces mouse liver fibrosis without blocking the innate immune response
dc.typeJournal article
pubs.publication-statusPublished

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