The role of redox-dependent mechanisms in the downregulation of ligand-induced Toll-like receptors 7, 8 and 4-mediated HIF-1 alpha prolyl hydroxylation.
Toll-like receptors (TLRs) are key components of the innate immune system that allow immune cells to specifically detect pathogens by recognizing their specific molecular patterns. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is known to have a critical role in TLR downstream signalling by promoting energy metabolism, expression of proinflammatory cytokines and proangiogenic factors. However, the molecular mechanisms leading to the accumulation of HIF-1 alpha are not fully understood. In this study, we report that R848 (specific ligand)-induced activation of endosomal TLRs 7 and 8 (which recognize viral single-stranded RNA) and lipopolysaccharide (LPS)-induced activation of TLR4 (which specifically recognizes LPS as a ligand) leads to downregulation of degradative HIF-1 alpha prolyl hydroxylation. In the case of TLR7/8, this downregulation is achieved through redox- and reactive nitrogen species (RNS)-dependent mechanisms. S-nitrosation of HIF-1 alpha protein was also observed. In the case of LPS-induced TLR4 activation, only a redox-dependent mechanism is involved. RNS and p38 MAP kinase (known to contribute to LPS-induced TLR4-dependent accumulation of HIF-1 alpha protein) do not affect HIF-1 alpha prolyl hydroxylation. In both cases, downregulation of HIF-1 alpha prolyl hydroxylation correlates with a decrease in intracellular iron (II).
Medway School of Pharmacy, University of Kent, Kent, UK.
Sally A
SA
Nicholas
Vadim V
VV
Sumbayev
D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006900:Hydroxylation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology*; D015538:Nitrosation / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000494:pharmacology; D026422:S-Nitrosoglutathione / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D008024:Ligands; D008070:Lipopolysaccharides; D026361:Reactive Nitrogen Species; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors; D026422:S-Nitrosoglutathione; D006861:Hydrogen Peroxide; D011393:Procollagen-Proline Dioxygenase; D048051:p38 Mitogen-Activated Protein Kinases; C402365:resiquimod