Lookup NU author(s): Saimir Luli,
Dr Lee Borthwick,
Dr Steven O'Reilly,
Professor Neil Perkins,
Professor Derek Mann,
Professor Fiona Oakley
Phosphorylation 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.
Author(s): Moles A, Sanchez AM, Banks PS, Murphy LB, Luli S, Borthwick L, Fisher A, O'Reilly S, van Laar JM, White SA, Perkins ND, Burt AD, Mann DA, Oakley F
Publication type: Article
Publication status: Published
Print publication date: 01/02/2013
ISSN (print): 0270-9139
ISSN (electronic): 1527-3350
Publisher: John Wiley & Sons, Inc.
PubMed id: 22996371
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