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Thrombin regulates matrix metalloproteinase-9 expression in human monocytes
Chi-Jen Chang1, Lung-An Hsu, Yu-Hsein Ko
1The First Cardiovascular Division, Chang-Gung University, Tao-Yuan, Taiwan.
Biochemical and Biophysical Research Communications
|May 21, 2009
Summary
Thrombin significantly increases matrix metalloproteinase-9 (MMP-9) secretion in human monocytes. This process involves protease-activated receptors (PARs), calcium mobilization, and activation of ERK1/2, p38, and NF-kappaB pathways.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- Thrombin is a key enzyme in blood coagulation.
- Matrix metalloproteinases (MMPs) play roles in tissue remodeling and inflammation.
- Monocytes are crucial immune cells involved in inflammatory processes.
Purpose of the Study:
- To investigate the regulation of matrix metalloproteinase-9 (MMP-9) expression by thrombin in human monocytes.
- To elucidate the signaling pathways involved in thrombin-induced MMP-9 production.
Main Methods:
- Gelatin zymography to assess MMP-9 secretion.
- Real-time RT-PCR and Western blot to analyze mRNA and protein levels.
- Inhibition studies using antibodies against protease-activated receptors (PARs), a calcium chelator (BAPTA), and kinase inhibitors (MEK, p38).
- Electromobility shift assay to detect NF-kappaB activation.
Main Results:
- Thrombin dose- and time-dependently increased MMP-9 secretion, mRNA, and protein levels in monocytes.
- Inhibition of PAR-1 and PAR-3 partially blocked thrombin's effect, with a synergistic effect when both were inhibited.
- Calcium mobilization was essential for thrombin-induced MMP-9 secretion.
- The ERK1/2 and p38 MAPK pathways, as well as NF-kappaB activation, were critical for thrombin-mediated MMP-9 up-regulation.
Conclusions:
- Thrombin significantly up-regulates MMP-9 expression in human monocytes.
- This regulation is mediated through PAR-1 and PAR-3 receptors, calcium signaling, and the activation of ERK1/2, p38, and NF-kappaB pathways.
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