期刊
IMMUNOLOGY AND CELL BIOLOGY
卷 88, 期 2, 页码 180-186出版社
WILEY
DOI: 10.1038/icb.2009.76
关键词
Toll-like receptors; inflammation; hypoxia-inducible factor 1; HIF-1 alpha prolyl hydroxylation
资金
- Royal Society [RG080474]
- Medway School of Pharmacy, University of Kent
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). Immunology and Cell Biology (2010) 88, 180-186; doi:10.1038/icb.2009.76; published online 20 October 2009
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