Regulation of 8-Hydroxydaidzein in IRF3-Mediated Gene Expression in LPS-Stimulated Murine Macrophages

Abstract

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 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) and polyinosinic:polycytidylic acid [Poly (I:C)] stimulated murine macrophage cell line (RAW264.7). The 8-HD downregulated the mRNA expression level of IRF-3-dependent genes by inhibiting phosphorylation of the IRF-3 transcription factor. The inhibitory mechanism of 8-HD in the IRF-3 signaling pathway was shown to inhibit the kinase activity of IKKε to phosphorylate IRF-3. This compound can also interfere with the TRIF-mediated complex formation composed of TRAF3, TANK, and IKKε leading to downregulation of AKT phosphorylation and reduction of IRF-3 activation, resulted in inhibition of IRF-3-dependent expression of genes including IFN-β, C-X-C motif chemokine 10 (CXCL10), and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1). Therefore, these results strongly suggest that 8-HD can act as a promising compound with the regulatory function of IRF-3-mediated inflammatory responses.

Caragana rosea Turcz Methanol Extract Inhibits Lipopolysaccharide-Induced Inflammatory Responses by Suppressing the TLR4/NF-κB/IRF3 Signaling Pathways

“…The Src tyrosine kinase is associated with a non-receptor membrane protein known to be active in carcinoma tissues [37]. Several publications agree that 70% of inflammatory and oncogenic processes code for that tyrosine kinase [38].…”

TANK Promotes Pressure Overload Induced Cardiac Hypertrophy via Activating AKT Signaling Pathway

“…Previous lecture showed that downregulation of TANK impaired AKT phosphorylation (19). Interrupting TRIF-mediated complex formation composed of TRAF3, TANK, and IKKε leaded to downregulation of AKT phosphorylation, and eventually downregulation of inflammation (48). Also, TANK-binding kinase 1(TBK1), which form a ternary complex with TANK and TRAF2 (13), which activates AKT by direct phosphorylation (49,50).…”

p38-dependent c-Jun degradation contributes to reduced PGE2 production in sodium orthovanadate-treated macrophages

“…Preparation of whole-cell lysates was done as described previously ( 18 ). Nuclear fractionation was done according to a previous report ( 18 ).…”

“…Preparation of whole-cell lysates was done as described previously ( 18 ). Nuclear fractionation was done according to a previous report ( 18 ). Immunoblotting analysis of both nuclear fractionation and whole-cell lysates was performed as indicated previously ( 18 ).…”