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Toll-like receptor-3-induced mitochondrial dysfunction in cultured human hepatocytes
Authors:Siamak Djafarzadeh  Madhusudanarao Vuda  Jukka Takala  Matthias Ochs  Stephan M Jakob
Institution:1. Department of Intensive Care Medicine, Inselspital, Bern University Hospital and University of Bern, 3010 Bern, Switzerland;2. Institute of Anatomy, University of Bern, 3012 Bern, Switzerland;2. Intensive Care Unit, Hospital São Camilo Pompéia;;3. Intensive Care Unit, Department of Medical Emergencies, Hospital das Clínicas, University of São Paulo;4. Intensive Care Unit, Hospital Sa¨o Camilo Santana, São Paulo, Brazil;2. Center of Physiology, Institute of Neurophysiology, University of Cologne, Cologne, Germany;3. Department of Urology, UZ Brussel, Brussels, Belgium;1. Unità Dipartimentale di Allergologia-Immunologia Clinica & Malattie Apparato Respiratorio, Ente Ospedaliero Fondazione Poliambulanza, Brescia, Italy;2. Unità di Igiene, Epidemiologia e Sanità Pubblica dell’Università degli Studi di Brescia, Brescia, Italy;3. Unità Operativa di Allergologia, Azienda Ospedaliero-Universitaria Integrata di Verona, Verona, Italy;4. Azienda Ospedaliera Cardarelli, Divisione di Pneumologia ad Indirizzo Allergologico, Napoli, Italy;6. Allergy and Respiratory Diseases, University of Genoa, Genova, Italy;5. Struttura Complessa di Pneumologia, Azienda Ospedaliero Universitaria S Maria della Misericordia di Udine, Udine, Italy;7. Pneumologia e Fisiopatologia Respiratoria, Azienda Ospedaliera Spedali Civili di Brescia, Brescia, Italy;11. Struttura Complessa di Pneumologia, ASL 2 Savonese, Pietra Ligure (SV), Italy;1. Parkinson Institute – Istituti Clinici di Perfezionamento, Milano, Italy;2. Biometry and Statistics Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;3. Nutrition and Dietetics Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;3. From the Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111 and;4. the Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, Québec H2W 1R7, Canada;1. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain;2. Centro de Estudios Avanzados de Cuba, Carretera San Antonio km 1 1/2, Valle Grande, La Lisa, Ciudad Habana CP 17100, Cuba;3. Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA;4. Instituto de Estructura de la Materia, Consejo Superior de Investigaciones Científicas IEM-CSIC, Serrano 121, 28006 Madrid, Spain;5. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nan Wei Road Street, Beijing 100050, China;6. Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA
Abstract:Several studies have shown the presence of liver mitochondrial dysfunction during sepsis. TLR3 recognizes viral double-stranded RNA and host endogenous cellular mRNA released from damaged cells. TLR3 ligand amplifies the systemic hyperinflammatory response observed during sepsis and in sepsis RNA escaping from damaged tissues/cells may serve as an endogenous ligand for TLR3 thereby modulating immune responses. This study addressed the hypothesis that TLR3 might regulate mitochondrial function in cultured human hepatocytes.HepG2 cells were exposed to TLR-3 ligand (dsRNA — polyinosine–polycytidylic acid; Poly I:C) and mitochondrial respiration was measured. Poly I:C induced a reduction in maximal mitochondrial respiration of human hepatocytes which was prevented partially by preincubation with cyclosporine A (a mitochondrial permeability transition pore-opening inhibitor). Poly-I:C induced activation of NF-κB, and the mitochondrial dysfunction was accompanied by caspase-8 but not caspase-3 activation and by no major alterations in cellular or mitochondrial ultrastructure.
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