Toll-like receptor-3-induced mitochondrial dysfunction in cultured human hepatocytes.
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.
Djafarzadeh
Siamak
S
Department of Intensive Care Medicine, Inselspital, Bern University Hospital and University of Bern, 3010 Bern, Switzerland.
Vuda
Madhusudanarao
M
Takala
Jukka
J
Ochs
Matthias
M
Jakob
Stephan M
SM
D053181:Caspase 8 / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016328:NF-kappa B; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016572:Cyclosporine; D053181:Caspase 8; D011070:Poly I-C