title: Transient knock down of Grp78 reveals roles in serum ferritin mediated pro-inflammatory cytokine secretion in rat primary activated hepatic stellate cells.
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 IL1β, 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.
authors.affiliation: School of Nutrition and Health Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan E-mail : susanchang@tmu.edu.tw, dhwcheng@tmu.edu.tw.
authors.forename: Chi-Mei
authors.initials: CM
authors.lastname: Wang
authors.forename: Shan-Jen
authors.initials: SJ
authors.lastname: Li
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Wu
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Hu
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Cheng
authors.forename: Jung-Su
authors.initials: JS
authors.lastname: Chang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005293:Ferritins / Q000097:blood / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000199:Actins; D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018836:Inflammation Mediators; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D005293:Ferritins