The involvement of hypoxia-inducible factor 1 alpha in Toll-like receptor 7/8-mediated inflammatory response.
Toll-like receptors (TLRs) 7 and 8 are crucial in host defence against single-stranded RNA (ssRNA) viruses. Such viruses cause severe illnesses, which remain a serious medical burden in both industrialised and developing countries. TLR7/8 downstream signaling leads to a dramatic cellular stress associated with energy consumption. However, the molecular mechanisms of cell survival and adaptation to TLR7/8-induced stress, which give the cells an opportunity to initiate proper inflammatory reactions, are not clear at all. Here we report for the first time that ligand-induced activation of TLR7/8 leads to the accumulation of hypoxia-inducible factor 1 alpha (HIF-1alpha) protein in THP-1 human myeloid macrophages via redox- and reactive nitrogen species-dependent mechanisms. MAP kinases and phosphoinositol-3K are not involved in TLR7/8-mediated HIF-1alpha accumulation. Experiments with HIF-1alpha knockdown THP-1 cells have clearly demonstrated that HIF-1alpha is important for the protection of these cells against TLR7/8-induced depletion of ATP. Thus, HIF-1alpha might support both cell survival and the production of pro-inflammatory cytokines upon TLR7/8 activation.
Nicholas
Sally A
SA
Medway School of Pharmacy, University of Kent, Kent ME4 4TB, UK.
Sumbayev
Vadim V
VV
D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology*; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D010084:Oxidation-Reduction; D012313:RNA / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D026361:Reactive Nitrogen Species; D015398:Signal Transduction; D013997:Time Factors; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D015850:Interleukin-6; D034741:RNA, Small Interfering; D026361:Reactive Nitrogen Species; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; C402365:resiquimod