Smad2 increases the apoptosis of activated human hepatic stellate cells induced by TRAIL |
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| Affiliation: | 1. School of Pharmacy, Anhui Medical University, Hefei 230032, China;2. Institute for Liver Diseases of Anhui Medical University (ILD-AMU), China;3. Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China;4. Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China;1. Laboratory of Immunogenetics of Diseases, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid 28046, Spain;2. Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid 28046, Spain;3. Immunology Unit, La Paz University Hospital, Madrid 28046, Spain;4. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA;5. Howard Hughes Medical Institute, New York, NY 10065, USA;6. Immunology Division, Vall d''Hebron University Hospital, Barcelona 08035, Spain;7. Laboratory of Tumour Immunology, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid 28046, Spain;8. Laboratory of Image and Immunohistochemistry, IdiPAZ Institute for Health Research, La Paz University Hospital, Madrid 28046, Spain;9. Clinical Immunology Department, San Carlos Clinical Hospital, Madrid 28040, Spain;10. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France;11. University Paris Descartes, Imagine Institute, Paris 75015, France;12. Paediatric Haematology-Immunology Unit, Necker Hospital for Sick Children, Paris 75015, France;1. Institut für Physiologie I, Robert-Koch-Str. 27a, D-48149 Münster, Germany;2. Department für Neurologie, Klinik für Allgemeine Neurologie and Institut für Physiologie, Abteilung für Neuropathophysiologie, Albert-Schweitzer-Campus 1, Westfälische Wilhelms-Universität, D-48149 Münster, Germany;1. National and Kapodistrian University of Athens, Medical School, MSc “Cardiopulmonary Resuscitation”, Athens, Greece;2. Hellenic Society of Cardiopulmonary Resuscitation, Athens, Greece;3. V.A. Negovsky Research Institute of General Reanimatology, Moscow, Russian Federation;4. Department of Public Health, Clinical and Molecular Medicine, Forensic Science Unit, University of Cagliari, Cagliari, Italy;5. European University of Cyprus, School of Medicine, Nicosia, Cyprus |
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| Abstract: | The activation of hepatic stellate cells (HSCs) plays a critical role in the development of liver fibrosis. The induction of apoptosis in activated HSCs during the recovery phase of hepatic fibrosis represents a potential anti-fibrotic therapy. We have previously shown that Smad2 protects against hepatic fibrogenesis; however, the role of Smad2 in the regulation of activated HSC apoptosis remains unknown. We hypothesized that Smad2 regulates the apoptosis of activated HSCs, leading to the resolution of liver fibrosis. To test this hypothesis, the livers of rats were harvested at 0 and 4 weeks after hepatic fibrosis was established by CCl4 injection. Furthermore, TGF-β1-activated HSCs were treated with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following the silencing or overexpression of Smad2. Both the phosphorylation of Smad2 and TRAIL were detected in fibrotic liver tissues. The results of TUNEL and α-SMA double-staining showed an increase in the apoptosis of activated HSCs during the spontaneous recovery phase. The knockdown of Smad2 reduced TRAIL-induced apoptosis in TGF-β1-activated human LX-2 cells and resulted in an increased expression of α-SMA and collagen I (Col. I). In contrast, the overexpression of Smad2 increased TRAIL-induced HSC apoptosis and reduced the expression of α-SMA and Col. I. The mechanisms underlying these findings were associated with the Smad2-mediated down-regulation of X-linked inhibitor of apoptosis protein (XIAP), resulting in enhanced caspase-3 activity and apoptosis. In conclusion, Smad2 enhances TRAIL-induced apoptosis in activated HSCs, which facilitates the resolution of hepatic fibrosis. |
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