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ADAM17 mediates MMP9 expression in lung epithelial cells
Ya-qing Li1, Jian-ping Yan, Wu-lin Xu
1Department of Respiratory Medicine, Zhejiang Provincial People's Hospital, Hangzhou, China.
Abstract:
The purposes were to study the role of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α/nuclear factor-κB (NF-κB) signaling in matrix metalloproteinase 9 (MMP9) expression in A549 cells and to investigate the effects of lentivirus-mediated RNAi targeting of the disintegrin and metalloproteinase 17 (ADAM17) gene on LPS-induced MMP9 expression. MMP9 expression induced by LPS in A549 cells was significantly increased in a dose- and time-dependent manner (p<0.05). Pyrrolidine dithiocarbamate (PDTC) and a TNFR1 blocking peptide (TNFR1BP) significantly inhibited LPS-induced MMP9 expression in A549 cells (p<0.05). TNFR1BP significantly inhibited LPS-induced TNF-α production (p<0.05). Both PDTC and TNFR1BP significantly inhibited the phosphorylation of IκBα and expression of phosphorylation p65 protein in response to LPS (p<0.05), and the level of IκBα in the cytoplasm was significantly increased (p<0.05). Lentivirus mediated RNA interference (RNAi) significantly inhibited ADAM17 expression in A549 cells. Lentivirus-mediated RNAi targeting of ADAM17 significantly inhibited TNF-α production in the supernatants (p<0.05), whereas the level of TNF-α in the cells was increased (p<0.05). Lentiviral ADAM17 RNAi inhibited MMP9 expression, IκBα phosphorylation and the expression of phosphorylation p65 protein in response to LPS (p<0.05). PDTC significantly inhibited the expression of MMP9 and the phosphorylation of IκBα, as well as the expression of phosphorylation p65 protein in response to TNF-α (p<0.05). Lentiviral RNAi targeting of ADAM17 down-regulates LPS-induced MMP9 expression in lung epithelial cells via inhibition of TNF-α/NF-κB signaling.
Insights
Lipopolysaccharide (LPS) increases matrix metalloproteinase 9 (MMP9) via tumor necrosis factor-alpha (TNF-α)/nuclear factor-kappa B (NF-κB) signaling. Targeting ADAM17 with RNA interference inhibits this LPS-induced MMP9 expression in lung cells.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Matrix metalloproteinase 9 (MMP9) plays a role in various physiological and pathological processes.
- Tumor necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB) signaling pathways are implicated in inflammatory responses and gene expression.
Purpose of the Study:
- To elucidate the role of TNF-α/NF-κB signaling in lipopolysaccharide (LPS)-induced MMP9 expression in A549 lung epithelial cells.
- To investigate the impact of targeting the disintegrin and metalloproteinase 17 (ADAM17) gene using lentivirus-mediated RNA interference (RNAi) on LPS-induced MMP9 expression.
Main Methods:
- Dose- and time-dependent analysis of LPS-induced MMP9 expression in A549 cells.
- Inhibition studies using pyrrolidine dithiocarbamate (PDTC) and a TNFR1 blocking peptide (TNFR1BP).
- Assessment of TNF-α production, IκBα phosphorylation, and p65 protein phosphorylation following LPS stimulation and ADAM17 RNAi.
Main Results:
- LPS significantly upregulated MMP9 expression in a dose- and time-dependent manner.
- PDTC and TNFR1BP inhibited LPS-induced MMP9 expression, TNF-α production, and NF-κB pathway activation.
- Lentivirus-mediated ADAM17 RNAi suppressed LPS-induced MMP9 expression by inhibiting TNF-α/NF-κB signaling.
Conclusions:
- LPS induces MMP9 expression in A549 cells through the TNF-α/NF-κB signaling pathway.
- Inhibition of ADAM17 expression via RNAi effectively downregulates LPS-induced MMP9 expression.
- Targeting ADAM17 presents a potential therapeutic strategy for conditions involving aberrant MMP9 activity in lung epithelial cells.
