H3K9 acetylation-NF-κB-AP-1 nexus targeted by ITE limits TNF-α-induced MMP-9 expression in monocytic cells

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• Matrix metalloproteinase 9 (MMP-9) is crucial in inflammatory disease pathogenesis and is upregulated by TNF-α.
• Indole-3-carbonyl-thiazole-4-carboxylic acid methyl ester (ITE) is an endogenous aryl hydrocarbon receptor ligand involved in inflammation.
• The effect of ITE on TNF-α-induced MMP-9 expression in monocytic cells remains unclear.

Purpose of the Study:

• To investigate the effect of ITE on TNF-α-induced MMP-9 expression in monocytic cells.
• To elucidate the underlying molecular mechanisms of ITE's action.

Main Methods:

• THP-1 monocytic cells and primary human monocytes were pretreated with ITE.
• TNF-α-induced MMP-9 expression was assessed at mRNA and protein levels.
• Epigenetic modifications (H3K9 acetylation), transcription factor binding (NF-κB, AP-1), and gene expression were analyzed.

Main Results:

• ITE pretreatment significantly inhibited TNF-α-induced MMP-9 expression in both cell types.
• ITE suppressed inflammatory gene expression and decreased H3K9 acetylation at the MMP-9 promoter.
• ITE inhibited TNF-α-induced NF-κB and AP-1 binding to the MMP-9 promoter.

Conclusions:

• ITE effectively reduces TNF-α-induced MMP-9 expression through epigenetic modulation of the H3K9 acetylation/NF-κB/AP-1 signaling axis.
• ITE's mechanism involves suppressing inflammatory pathways and transcription factor binding.
• ITE presents a potential therapeutic agent for mitigating MMP-9-related inflammatory disorders.