Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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Transient Knock Down of Grp78 Reveals Roles in Serum Ferritin Mediated Pro-inflammatory Cytokine Secretion in Rat Primary Activated Hepatic Stellate Cells

  • Wang, Chi-Mei (School of Nutrition and Health Sciences, College of Public Health and Nutrition) ;
  • Li, Shan-Jen (Department of Emergency Medicine, Taipei Medical University Hospital) ;
  • Wu, Chi-Hao (School of Nutrition and Health Sciences, College of Public Health and Nutrition) ;
  • Hu, Chien-Ming (Department of Emergency Medicine, Taipei Medical University Hospital) ;
  • Cheng, Hui-Wen (School of Pharmacy, College of Pharmacy, Taipei Medical University) ;
  • Chang, Jung-Su (School of Nutrition and Health Sciences, College of Public Health and Nutrition)
  • Published : 2014.01.30
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Abstract

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 $IL1{\beta}$, IL6 and $TNF{\alpha}$ secretion in rat activated HSCs (all p<0.05). By contrast, treatment did not alter activation marker ${\alpha}SMA$ 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 $IL1{\beta}$ and $TNF{\alpha}$ 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.

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