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Involvement of xanthine oxidase and hypoxia-inducible factor 1 in Toll-like receptor 7/8-mediated activation of caspase 1 and interleukin-1β

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Abstract

Inflammatory reactions to ssRNA viruses are induced by the endosomal Toll-like receptors (TLRs) 7 and 8. TLR7/8-mediated inflammatory reaction results in activation of the Nalp3 inflammasome via an unknown mechanism. Here we report for the first time that TLR7/8 mediate activation of xanthine oxidase (XOD) in an HIF-1α-dependent manner. XOD produces uric acid and reactive oxygen species, which could activate Nalp3 and therefore induce activation of caspase 1, known to convert inactive pro-IL-1β into active IL-1β. Specific inhibition of the XOD activity attenuates TLR7/8-mediated activation of caspase 1 and IL-1β release. These results were obtained using human THP-1 myeloid macrophages. The findings were verified by conducting in vivo experiments on mice.

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Acknowledgments

This work was supported by the Royal Society (Grant number RG080474 to Dr. V. Sumbayev) and by the start-up grant provided to Dr. Sumbayev by the Medway School of Pharmacy, University of Kent.

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Authors and Affiliations

  1. Medway School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent, ME4 4TB, UK

    Sally A. Nicholas, Inna M. Yasinska & Vadim V. Sumbayev

  2. Odessa State Medical University, Odessa, Ukraine

    Vladimir V. Bubnov

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  1. Sally A. Nicholas
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  2. Vladimir V. Bubnov
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  3. Inna M. Yasinska
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  4. Vadim V. Sumbayev
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Correspondence to Vadim V. Sumbayev.

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Nicholas, S.A., Bubnov, V.V., Yasinska, I.M. et al. Involvement of xanthine oxidase and hypoxia-inducible factor 1 in Toll-like receptor 7/8-mediated activation of caspase 1 and interleukin-1β. Cell. Mol. Life Sci. 68, 151–158 (2011). https://doi.org/10.1007/s00018-010-0450-3

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  • DOI: https://doi.org/10.1007/s00018-010-0450-3

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