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Article first published online: 8 JAN 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 2, pages 817–828, February 2013
How to Cite
Moles, A., Sanchez, A. M., Banks, P. S., Murphy, L. B., Luli, S., Borthwick, L., Fisher, A., O'Reilly, S., van Laar, J. M., White, S. A., Perkins, N. D., Burt, A. D., Mann, D. A. and Oakley, F. (2013), Inhibition of RelA-Ser536 phosphorylation by a competing peptide reduces mouse liver fibrosis without blocking the innate immune response. Hepatology, 57: 817–828. doi: 10.1002/hep.26068
Potential conflict of interest: Nothing to report.
This work was funded by grants from a UK Medical Research Council (MRC) New Investigator Research Grant (G0900535; to F.O.), the UK MRC (G0700890; to D.A.M. and F.O.), and the Wellcome Trust (WT084961MA; to F.O. and D.A.M.). A Wellcome Trust equipment grant (WT 087961) provided the in vivo imaging system–funded purchase.
- Issue published online: 5 FEB 2013
- Article first published online: 8 JAN 2013
- Accepted manuscript online: 19 SEP 2012 11:32AM EST
- Manuscript Accepted: 29 AUG 2012
- Manuscript Revised: 24 MAY 2012
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. (HEPATOLOGY 2013)