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Interferonopathies are rare genetic conditions defined by systemic inflammatory episodes caused by innate immune system activation in the absence of pathogens. Currently, no targeted drugs are authorized for clinical use in these diseases. In this work, we studied the contribution of sulforaphane (SFN), a cruciferous-derived bioactive molecule, in the modulation of interferon-driven inflammation in an immortalized human hepatocytes (IHH) line and in two healthy volunteers, focusing on <i>STING</i>, a key-component player in interferon pathway, interferon signature modulation, and <i>GSTM1</i> expression and genotype, which contributes to SFN metabolism and excretion. In vitro, SFN exposure reduced <i>STING</i> expression as well as interferon signature in the presence of the pro-inflammatory stimulus cGAMP (cGAMP 3 h vs. SFN+cGAMP 3 h <i>p</i> value < 0.0001; cGAMP 6 h vs. SFN+cGAMP 6 h <i>p</i> < 0.001, one way ANOVA), restoring STING expression to the level of unstimulated cells. In preliminary experiments on healthy volunteers, no appreciable variations in interferon signature were identified after SFN assumption, while only in one of them, presenting the <i>GSTM1</i> wild type genotype related to reduced SFN excretion, could a downregulation of <i>STING</i> be recorded. This study confirmed that SFN inhibits <i>STING</i>-mediated inflammation and interferon-stimulated genes expression in vitro. However, only a trend towards the downregulation of <i>STING</i> could be reproduced in vivo. Results obtained have to be confirmed in a larger group of healthy individuals and in patients with type I interferonopathies to define if the assumption of SFN could be useful as supportive therapy.