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

• Published in: Immunology and cell biology 2010-02, Vol.88 (2), p.180
• Main Authors: Nicholas, Sally A, Sumbayev, Vadim V
• Format: Article
• Language: English
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.2009.76

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-1α (HIF-1α) 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-1α 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-1α 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-1α 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-1α protein) do not affect HIF-1α prolyl hydroxylation. In both cases, downregulation of HIF-1α prolyl hydroxylation correlates with a decrease in intracellular iron (II).