Transient Knock Down of Grp78 Reveals Roles in Serum Ferritin Mediated Pro-inflammatory Cytokine Secretion in Rat Primary Activated Hepatic Stellate Cells

Chi-Mei Wang, Shan-Jen Li, Chi-Hao Wu, Chien-Ming Hu, Hui-Wen Cheng, Jung-Su Chang
2014 Asian Pacific Journal of Cancer Prevention  
Chronic liver diseases, including cancer, are characterized by inflammation and elevated serum ferritin (SF). However, the causal-relationship remains unclear. This study used primary rat hepatic stellate cells (HSC) as a model to investigate effects of physiological SF concentrations (10, 100 and 1000 pM) because HSCs play a central role in the development and progression of liver fibrosis. Physiological concentrations of SF, either horse SF or human serum, induced pro-inflammatory cytokine
more » ... β, IL6 and TNFα secretion in rat activated HSCs (all p<0.05). By contrast, treatment did not alter activation marker αSMA expression. The presence of SF markedly enhanced expression of Grp78 mRNA (p<0.01). Furthermore, transient knock down of Grp78 by endotoxin EGF-SubA abolished SF-induced IL1β and TNFα secretion in activated HSCs (all p<0.05). In conclusion, our results showed that at physiological concentrations SF functions as a pro-inflammatory mediator in primary rat HSCs. We also provide a molecular basis for the action of SF and identified Grp78-associated ER stress pathways as a novel potential therapeutic target for resolution of fibrosis and possible prevention of liver cancer.
doi:10.7314/apjcp.2014.15.2.605 fatcat:frf6wghz3vegxg24prlki6724y