NF-κB is a critical regulator of the survival of rodent and human hepatic myofibroblasts

• Published in: Journal of hepatology 2008-04, Vol.48 (4), p.589-597
• Main Authors: Watson, Martha R, Wallace, Karen, Gieling, Roben G, Manas, Derek M, Jaffray, Ellis, Hay, Ronald T, Mann, Derek A, Oakley, Fiona
• Format: Article
• Language: English
• Subjects: Apoptosis; Biological and medical sciences; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Hepatic myofibroblast; Liver fibrosis; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; NF-κB (NF-kappaB); Other diseases. Semiology
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2007.12.019

Background/Aims Hepatic myofibroblast activation during injury causes deposition of extracellular matrix within the liver and promotes development of fibrosis. Hepatic myofibroblast apoptosis is associated with remodelling of fibrotic extracellular matrix and regression of fibrosis. Previous work showed that inhibition of constitutive NF-κB signaling promotes hepatic myofibroblast apoptosis and resolution of fibrosis in rodent models. However, to date agents used to target constitutive NF-κB transcriptional activity in hepatic myofibroblasts have been relatively non-specific with potential for off-target effects that may complicate data interpretation. Likewise, rat chronic liver disease models may not accurately recapitulate the activation of human hepatic myofibroblasts. Methods We used a mutant recombinant IκBα super-repressor fused to the HIV–TAT domain to specifically target NF-κB signaling in hepatic myofibroblasts. Inhibition of NF-κB activity was measured using reporter assay. Apoptosis of hepatic myofibroblasts was assessed by morphological changes, cleavage of the PARP-1 protein and Caspase 3 activation. Results TAT-IκBαSR reduced NF-κB dependent transcription, Bcl-2 expression and promoted Jun-N-terminal kinase-dependent apoptosis in human and rat hepatic myofibroblasts. Conclusions These data highlight the conserved role of NF-κB during fibrogenesis. Our data validate the use of rodent models for pre-clinical testing of NF-κB inhibitors as anti-fibrotics and stimulators of fibrotic extracellular matrix remodelling.