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Lithium chloride suppresses LPS-mediated matrix metalloproteinase-9 expression in macrophages through phosphorylation
Sooho Kim1, Naeun Bong, Ok Soo Kim
1Laboratory of Genome to Drug Medicine, Joint Center for Biosciences, 7-45 Songdo-dong, Yeonsu-ku, Incheon, Korea.
Abstract:
Abnormal degradation of matrix components due to dysregulated expression of matrix metalloproteinase (MMP)-9 in macrophages has been linked to progression of acute cerebral ischemia and atherosclerosis. We report that lithium chloride (LiCl) or CHIR99021, inhibitors of Wnt signaling pathway, enhance phosphorylation of glycogen synthase kinase-3beta and suppress lipopolysaccharide-mediated upregulation of MMP-9 expression in murine macrophage RAW264.7 cells in a dose-dependent manner. Suppression of MMP-9 expression by LiCl or CHIR99021 did not result after inhibition of kinases involved in NFκB or AP-1 family proteins, but from changes in the activity of histone deacetylases. Beneficial effects on atherosclerosis or cerebral ischemia in animal studies caused by LiCl may be in part explained by the suppression of MMP-9 gene expression.
Insights
Lithium chloride (LiCl) and CHIR99021 suppress matrix metalloproteinase-9 (MMP-9) in macrophages by altering histone deacetylase activity. This finding may explain LiCl
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Matrix metalloproteinase-9 (MMP-9) dysregulation in macrophages contributes to acute cerebral ischemia and atherosclerosis progression.
- Understanding MMP-9 regulation is crucial for developing therapeutic strategies against these conditions.
Purpose of the Study:
- To investigate the effects of Wnt signaling inhibitors on MMP-9 expression in macrophages.
- To elucidate the molecular mechanisms underlying MMP-9 suppression by lithium chloride (LiCl) and CHIR99021.
Main Methods:
- Utilized murine macrophage RAW264.7 cells.
- Administered LiCl and CHIR99021, Wnt signaling pathway inhibitors.
- Assessed lipopolysaccharide-mediated MMP-9 expression.
- Investigated the role of glycogen synthase kinase-3beta phosphorylation, NFκB, AP-1, and histone deacetylase activity.
Main Results:
- LiCl and CHIR99021 dose-dependently enhanced glycogen synthase kinase-3beta phosphorylation.
- These inhibitors suppressed lipopolysaccharide-induced upregulation of MMP-9 expression.
- MMP-9 suppression was linked to changes in histone deacetylase activity, not NFκB or AP-1 pathways.
Conclusions:
- Wnt signaling inhibition, via LiCl or CHIR99021, effectively suppresses MMP-9 expression in macrophages.
- The mechanism involves histone deacetylase modulation.
- These findings provide a molecular basis for the beneficial effects of LiCl in animal models of atherosclerosis and cerebral ischemia.
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