ORIGINAL ARTICLE

Cell Research (2009): 1-11
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The involvement of hypoxia-inducible factor 1 alpha in Toll-like receptor 7/8-mediated inflammatory response

Sally A Nicholas and Vadim V Sumbayev

Correspondence: Vadim V Sumbayev, Tel: +44-1634-883-868; Fax +44-1634-883-927 E-mail: V.Sumbayev@kent.ac.uk

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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-1α) 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-1α accumulation. Experiments with HIF-1α knockdown THP-1 cells have clearly demonstrated that HIF-1α is important for the protection of these cells against TLR7/8-induced depletion of ATP. Thus, HIF-1α might support both cell survival and the production of pro-inflammatory cytokines upon TLR7/8 activation.

Cell Research advance online publication 21 April 2009; doi: 10.1038/cr.2009.44

Keywords: inflammation and innate immunity, Toll-like receptors, HIF-1 protein, apoptosis