title: Receptor-specific TRAIL as a means to achieve targeted elimination of activated hepatic stellate cells.
abstract: Activated hepatic stellate cells (HSCs) are known to play a central role in liver fibrosis and their elimination is a crucial step toward the resolution and reversion of liver fibrosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a molecule that may contribute to the apoptotic removal of activated HSC through binding to its dedicated receptors. In the present study, we investigated the potential application of recombinant receptor-specific TRAIL proteins in the efficient elimination of activated HSCs. Our finding revealed differential contribution of TRAIL receptors among HSCs populations with activated hepatic stellate cells expresses more TRAIL receptors DR5. In vitro treatment of activated HSCs with DR5-specific or wild-type TRAIL variants induced a significant reduction in viability and extracellular matrix production, whereas no significant decrease in viability was associated with the treatment of cells by DR4-specific TRAIL. Our analysis indicate the successful application of the DR5 receptor-specific TRAIL variant in the targeted elimination of activated HSCs via interference with collagen production and simultaneous induction of apoptosis via activation of the caspase pathway. DR5 receptor-specific TRAIL may thus represent a new therapeutic compound for the treatment of liver fibrosis.
authors.affiliation: a Mivac Development , Arvid Wallgrens backe 20 , Gothenburg , Sweden.|b Department of Chemical and Pharmaceutical Biology , University of Groningen , Groningen , the Netherlands.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Arabpour
authors.affiliation: b Department of Chemical and Pharmaceutical Biology , University of Groningen , Groningen , the Netherlands.
authors.forename: Robbert H
authors.initials: RH
authors.lastname: Cool
authors.affiliation: c Department of Gastrointestinal and Liver Diseases , University Medical Center Groningen , Groningen , the Netherlands.
authors.forename: Klaas Nico
authors.initials: KN
authors.lastname: Faber
authors.affiliation: b Department of Chemical and Pharmaceutical Biology , University of Groningen , Groningen , the Netherlands.
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Quax
authors.affiliation: b Department of Chemical and Pharmaceutical Biology , University of Groningen , Groningen , the Netherlands.
authors.forename: Hidde J
authors.initials: HJ
authors.lastname: Haisma
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002461:Cell Line, Transformed; D004591:Electrophoresis, Polyacrylamide Gel; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand
keywords: Liver fibrosis; hepatic stellate cell; receptor-specific TRAIL; targeted therapy