Naslov
New mechanism of selective killing of activated hepatic stellate cells

Autori
Dodig, Milan ; Mullen Kevin D.

Izvornik
Hepatology (0270-9139) 38 (2003), 4; 1051-1053

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
hepatology ; selective killing ; hepatic stellate cells

Sažetak
Background & Aims: 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.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA