Proteasome inhibition induces hepatic stellate cell apoptosis.
Journal - Hepatology (Baltimore, Md.) (United States )
Induction of hepatic stellate cell (HSC) apoptosis attenuates hepatic fibrosis, and, therefore, mechanisms to induce HSC cell death are of therapeutic interest. Proteasome inhibitors induce apoptosis in transformed cells, especially those cells dependent upon nuclear factor kappa B (NF-kappaB) activation. Because stimulated HSCs also trigger NF-kappaB activation, the aim of this study was to determine if proteasome inhibitors induce HSC apoptosis. The immortalized human HSC line, LX-2, and primary rat HSCs were treated with the proteasome inhibitors bortezomib and MG132. Both proteasome inhibitors induced HSC apoptosis. Proteasome inhibition blocked NF-kappaB activation and, more importantly, NF-kappaB inhibition by Bay11-7082-triggered HSC apoptosis. Activated HSC survival is dependent upon the NF-kappaB target gene A1, an anti-apoptotic Bcl-2 family member, as siRNA targeted knockdown of A1-induced HSC apoptosis. In contrast, proteasome inhibition-induced alterations in TRAIL, death receptor 5, and Bim could not be implicated in the apoptotic response. The relevance of these findings was confirmed in the bile-duct-ligated mouse where bortezomib reduced hepatic markers of stellate cell activation and fibrosis. In conclusion, proteasome inhibition is a potential therapeutic strategy for inducing HSC apoptosis and inhibiting liver fibrogenesis.
|ISSN : ||0270-9139|
|Mesh Heading : ||Animals Apoptosis Bile Ducts Boronic Acids Cell Line Humans Leupeptins Ligation Liver Liver Cirrhosis Mice NF-kappa B Proteasome Endopeptidase Complex Proto-Oncogene Proteins c-bcl-2 Pyrazines Rats Receptors, TNF-Related Apoptosis-Inducing Ligand Receptors, Tumor Necrosis Factor drug effects physiology pharmacology drug effects physiology biosynthesis|
|Mesh Heading Relevant : ||physiology pharmacology cytology physiopathology biosynthesis antagonists & inhibitors pharmacology|
Proteasome inhibition attenuates hepatic injury in the bile duct-ligated mouse.
Journal - American journal of physiology. Gastrointestinal and liver physiology (United States )
Proteasome inhibition has recently been demonstrated to inhibit hepatic fibrogenesis in the bile duct-ligated (BDL) mouse by blocking stellate cell NF-kappaB activation. The effect of proteasome inhibition on liver injury, however, is unclear. Our aims were to assess the effect of the proteasome inhibitor bortezomib on liver injury in the BDL mouse. Liver injury was assessed in 7-day BDL mice treated with a single dose of bortezomib on day 4 after bile duct ligation. Despite NF-kappaB inhibition by bortezomib, liver injury and hepatocyte apoptosis were reduced in treated BDL mice. The antiapoptotic effect of bortezomib was likely mediated by an increase in hepatic cellular FLICE inhibitory protein (c-FLIP) levels, a potent antiapoptotic protein. Unexpectedly, numerous mitotic hepatocytes were observed in the bortezomib-treated BDL mice liver specimens. Consistent with this observation, PCNA immunoreactivity and cyclin A protein expression were also increased with bortezomib treatment. Bortezomib therapy was also associated with a decrease in numbers and activation of Kupffer cells/macrophages. In conclusion, these data suggest that the proteasome inhibitor bortezomib reduces hepatocyte injury in the BDL mouse by mechanisms associated with a reduction in hepatocyte apoptosis, a decrease in Kupffer cell/macrophage number and activation, and increased hepatocyte proliferation.
|ISSN : ||0193-1857|
|Mesh Heading : ||Animals Bile Ducts Boronic Acids Cell Count Cholestasis Hepatocytes Liver Cirrhosis Macrophage Activation Macrophages Mice NF-kappa B Protease Inhibitors Proteasome Endopeptidase Complex Pyrazines pathology metabolism drug therapy metabolism|
|Mesh Heading Relevant : ||pharmacology drug therapy metabolism pharmacology antagonists & inhibitors pharmacology|