Caspase 9-dependent killing of hepatic stellate cells by activated Kupffer cells.
OBJECTIVE
Hepatic stellate cells play an important role in liver fibrogenesis, and hepatic stellate cell death may be involved in the termination of this response.


METHODS
Molecular mechanisms of hepatic stellate cell killing were studied in hepatic stellate cell/Kupffer cell cocultures.


RESULTS
Lipopolysaccharide stimulation of hepatic stellate cell/Kupffer cell cocultures, but not of hepatic stellate cell monocultures, induced profound alterations of hepatic stellate cell morphology and hepatic stellate cell death. Kupffer cell-induced hepatic stellate cell killing required hepatic stellate cell/Kupffer cell contacts and was prevented by dexamethasone, prostaglandin E(2), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 antagonists, and down-regulation of receptor-interacting protein, but not by antioxidants, tumor necrosis factor receptor, or CD95 antagonists. Hepatic stellate cell death was characterized by activation of caspases 3, 8, and 9, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling negativity, lack of gross calcium overload, and TRAIL trafficking to the plasma membrane. Inhibition of caspase 9, but not of caspases 3, 8, or 10, prevented hepatic stellate cell death. Lipopolysaccharide induced a dexamethasone- and prostaglandin E(2)-sensitive expression of TRAIL in Kupffer cells. TRAIL receptors 1 and 2, FLIP (caspase 8-inhibitory protein), and receptor-interacting protein were up-regulated during hepatic stellate cell transformation; however, TRAIL addition did not induce hepatic stellate cell death. Hepatic stellate cell susceptibility toward Kupffer cell-induced death paralleled receptor-interacting protein and TRAIL-receptor expression levels.


CONCLUSIONS
Activated Kupffer cell can effectively kill hepatic stellate cell by a caspase 9- and receptor-interacting protein-dependent mechanism, possibly involving TRAIL. The data may suggest a novel form of hepatic stellate cell death.
Fischer
Richard
R
Department of Gastroenterology, Hepatology and Infectiology, Medizinische Einrichtungen der Heinrich-Heine Universität, Düsseldorf, Germany.
Cariers
Alexandra
A
Reinehr
Roland
R
Häussinger
Dieter
D
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002118:Calcium / Q000502:physiology; D053453:Caspase 9; D020169:Caspases / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D007425:Intracellular Membranes / Q000378:metabolism; D007728:Kupffer Cells / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D011506:Proteins / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011506:Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505655:Tnfsf10 protein, rat; D014409:Tumor Necrosis Factor-alpha; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases; D002118:Calcium