Regulation of TRAF3-IKK interaction by an 8-hydroxydaidzein contributed to the inhibitory effect on the IRF-3 signaling pathway

Cytokines and chemokines are transcriptionally regulated by inflammatory transcription factors such as nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and interferon regulatory factor (IRF)-3. A daidzein derivative compound, 8-hydroxydaidzein (8-HD), isolated from fermented soy products, has recently gained attention due to various pharmacological benefits, including anti-inflammatory activities. However, regulation of the inflammatory signaling mechanism for 8-HD is still poorly understood, particularly with respect to the IRF-3 signaling pathway. In this study, we explored the molecular mechanism of 8-HD in regulating inflammatory processes, with a focus on the IRF-3 signaling pathway using a lipopolysaccharide (LPS)-stimulated murine macrophage cell line (RAW264.7). The 8-HD downregulated the mRNA expression level of IRF-3-dependent genes by inhibiting phosphorylation of IRF-3 transcription factor. The inhibitory mechanism of 8-HD in the IRF-3 signaling pathway partly relies on the ability of 8-HD to inhibit TRAF3 and IKK interaction, which subsequently downregulates phosphorylation of AKT and reduces activation of IRF-3, thereby mediating inhibition of IRF-3-dependent gene transcription such as that of IFN-β, C-X-C motif chemokine 10 (CXCL10), and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1).

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