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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- Nicholas, S.A., Bubnov, V.V., Yasinska, I.M. et al. Cell. Mol. Life Sci. (2011) 68: 151. doi:10.1007/s00018-010-0450-3
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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.