title: Endotoxin-stimulated Rat Hepatic Stellate Cells Induce Autophagy in Hepatocytes as a Survival Mechanism.
abstract: Bacterial lipopolysaccharide (LPS)-stimulated hepatic stellate cells (HSCs) produce many cytokines including IFNβ, TNFα, and IL6, strongly inhibit DNA synthesis, but induce apoptosis of a small number of hepatocytes. In vivo administration of LPS (up to 10 mg/mL) causes modest inflammation and weight loss in rats but not mortality. We determined whether LPS-stimulated HSCs instigate mechanisms of hepatocyte survival. Rats received 10 mg/kg LPS (i.p.) and determinations were made at 6 h. In vitro, HSCs were treated with 100 ng/mL LPS till 24 h. The medium was transferred to hepatocytes, and determinations were made at 0-12 h. Controls were HSC-conditioned medium or medium-containing LPS. LPS treatment of rats caused autophagy in hepatocytes, a physiological process for clearance of undesirable material including injured or damaged organelles. This was accompanied by activation of c-Jun NH2 terminal kinase (JNK) and apoptosis of ~4-5% of hepatocytes. In vitro, LPS-conditioned HSC medium (LPS/HSC) induced autophagy in hepatocytes but apoptosis of only ~10% of hepatocytes. While LPS/HSC stimulated activation of JNK (associated with cell death), it also activated NFkB and ERK1/2 (associated with cell survival). LPS-stimulated HSCs produced IFNβ, and LPS/HSC-induced autophagy in hepatocytes and their apoptosis were significantly inhibited by anti-IFNβ antibody. Blockade of autophagy, on the other hand, strongly augmented hepatocyte apoptosis. While LPS-stimulated HSCs cause apoptosis of a subpopulation of hepatocytes by producing IFNβ, they also induce cell survival mechanisms, which may be of critical importance in resistance to liver injury during endotoxemia.
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.|Department of Surgery, University of Cincinnati, and Cincinnati VA Medical Center, Cincinnati, Ohio.|Cincinnati VA Medical Center, Cincinnati, Ohio.
authors.forename: Anil
authors.initials: A
authors.lastname: Dangi
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.|Department of Surgery, University of Cincinnati, and Cincinnati VA Medical Center, Cincinnati, Ohio.
authors.forename: Ashish
authors.initials: A
authors.lastname: Tandon
authors.affiliation: Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Donna
authors.initials: D
authors.lastname: Stolz
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.|Department of Surgery, University of Cincinnati, and Cincinnati VA Medical Center, Cincinnati, Ohio.|Cincinnati VA Medical Center, Cincinnati, Ohio.|Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Chandrashekhar R
authors.initials: CR
authors.lastname: Gandhi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017207:Rats, Sprague-Dawley
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides