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Hypoxia inducible factor‐1α induction by tumour necrosis factor‐α, but not by toll‐like receptor agonists, modulates cellular respiration in cultured human hepatocytes
Author(s) -
Regueira Tomas,
Lepper Philipp M.,
Brandt Sebastian,
Ochs Matthias,
Vuda Madhusudanarao,
Takala Jukka,
Jakob Stephan M.,
Djafarzadeh Siamak
Publication year - 2009
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2009.02109.x
Subject(s) - hypoxia inducible factors , toll like receptor , hypoxia (environmental) , receptor , tumor necrosis factor alpha , respiration , necrosis , chemistry , microbiology and biotechnology , cancer research , pharmacology , biology , immunology , medicine , biochemistry , anatomy , innate immune system , oxygen , gene , organic chemistry
Background/Aims: Genes encoding for some of the mitochondrial proteins are under the control of the transcriptional factor hypoxia inducible factor‐1α (HIF‐1α), which can accumulate under normoxic conditions in inflammatory states. The aim of this study was to evaluate the effects of cobalt chloride (CoCl 2 , a hypoxia mimicking agent), tumour necrosis factor‐α (TNF‐α) and toll‐like receptor (TLR) ‐2, ‐3 and ‐4 agonists on HIF‐1α accumulation, and further on HIF‐1α‐mediated modulation of mitochondrial respiration in cultured human hepatocytes. Methods: The human hepatoma cell line HepG2 was used in this study. Cells were treated with CoCl 2 , TNF‐α and TLR‐2, ‐3 and ‐4 agonists. HIF‐1α was determined by Western blotting and mitochondrial respiration in stimulated cells by high‐resolution respirometry. Results: CoCl 2 , TNF‐α and TLR agonists induced the expression of HIF‐1α in a time‐dependent fashion. TNF‐α and CoCl 2 , but not TLR agonists, induced a reduction in complex I‐, II‐ and IV‐dependent mitochondrial oxygen consumption. TNF‐α‐associated reduction of cellular oxygen consumption was abolished through inhibition of HIF‐1α activity by chetomin (CTM). Pretreatment with cyclosporine A prevented CoCl 2 ‐induced reduction of complex I‐ and II‐dependent mitochondrial oxygen consumption and TNF‐α‐induced reduction of complex‐I‐dependent respiration, implicating the involvement of the mitochondrial permeability transition pore openings. TNF‐α and TLR‐2, ‐3 and ‐4 agonists induced the expression of vascular endothelial growth factor, which was partially abolished by the blockage of HIF‐1α with CTM. Conclusions: The data suggest that HIF‐1α modulates mitochondrial respiration during CoCl 2 and TNF‐α stimulation, whereas it has no effect when induced with TLR‐2, ‐3 and ‐4 agonists.