Bahman Fatemah, Akhter Nadeem, Kochumon Shihab, Al-Mulla Fahd, Ahmad Rasheed
Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait.
Translational Research Department, Dasman Diabetes Institute, Dasman 15462, Kuwait.
Int J Mol Sci. 2025 Jun 13;26(12):5663. doi: 10.3390/ijms26125663.
Matrix metalloproteinase-9 (MMP-9) and lipopolysaccharide (LPS) levels are known to be elevated in obesity and contribute to metabolic dysfunction. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous ligand of the aryl hydrocarbon receptor (AhR), has been implicated in the regulation of inflammatory responses. This study aimed to determine whether ITE can inhibit LPS-induced MMP-9 expression in monocytic cells and to explore the underlying signaling mechanisms involved. Human monocytic THP-1 cells and primary human monocytes were treated with LPS in the presence or absence of ITE. MMP-9 mRNA and protein levels were assessed using quantitative real-time PCR and ELISA, respectively, while gelatin zymography was employed to evaluate MMP-9 enzymatic activity. Chromatin immunoprecipitation followed by qPCR (ChIP-qPCR) was performed to assess NF-κB and AP-1 binding to the MMP-9 promoter region. Our findings demonstrate that ITE significantly suppresses LPS-induced MMP-9 gene and protein expression. This suppression is associated with a marked reduction in LPS-induced NF-κB and AP-1 transcriptional activity. ChIP-qPCR confirmed that ITE attenuates the recruitment of NF-κB and AP-1 to the MMP-9 promoter, thereby inhibiting its transcription. In summary, ITE downregulates LPS-induced MMP-9 expression by interfering with NF-κB/AP-1 signaling, suggesting a potential anti-inflammatory mechanism that could be relevant in the context of MMP-9-driven inflammatory conditions.
已知基质金属蛋白酶-9（MMP-9）和脂多糖（LPS）水平在肥胖症中会升高，并导致代谢功能障碍。2-（1'H-吲哚-3'-羰基）-噻唑-4-羧酸甲酯（ITE）是芳烃受体（AhR）的内源性配体，与炎症反应的调节有关。本研究旨在确定ITE是否能抑制单核细胞中LPS诱导的MMP-9表达，并探索其潜在的信号传导机制。在有或没有ITE的情况下，用人单核THP-1细胞和原代人单核细胞进行LPS处理。分别使用定量实时PCR和ELISA评估MMP-9 mRNA和蛋白水平，同时采用明胶酶谱法评估MMP-9酶活性。进行染色质免疫沉淀后qPCR（ChIP-qPCR）以评估NF-κB和AP-1与MMP-9启动子区域的结合。我们的研究结果表明，ITE能显著抑制LPS诱导的MMP-9基因和蛋白表达。这种抑制与LPS诱导的NF-κB和AP-1转录活性的显著降低有关。ChIP-qPCR证实，ITE减弱了NF-κB和AP-1向MMP-9启动子的募集，从而抑制其转录。总之，ITE通过干扰NF-κB/AP-1信号传导下调LPS诱导的MMP-9表达，提示一种可能与MMP-9驱动的炎症状态相关的潜在抗炎机制。
