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Manganese modulates pro-inflammatory gene expression in activated glia
Chun-Jung Chen1, Yen-Chuan Ou, Shih-Yi Lin
1Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan. cjchen@vghtc.gov.tw
Neurochemistry International
|February 21, 2006
Summary
Manganese exposure can worsen central nervous system inflammation by boosting pro-inflammatory responses in glial cells. This study reveals how manganese affects glial cells, impacting neuroinflammation and potential neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Redox-active metals, like manganese, are crucial for biological functions but excessive exposure can lead to neurotoxicity.
- Manganese neurotoxicity is linked to the activation of microglia and astrocytes, the primary immune cells in the central nervous system (CNS).
Purpose of the Study:
- To investigate the molecular mechanisms by which manganese affects pro-inflammatory cytokine and nitric oxide (NO) production in primary rat cortical glial cells.
- To understand manganese's role in modulating glial inflammatory responses.
Main Methods:
- Primary rat cortical glial cells (85% astrocytes, 15% microglia) were cultured and exposed to varying manganese concentrations.
- Cells were stimulated with lipopolysaccharide/interferon-gamma to assess manganese's effect on pro-inflammatory cytokine and nitric oxide synthase expression and activity.
- Molecular analyses included gene expression, protein activation (MAPK, NF-κB, AP-1), and cofactor activity assays.
Main Results:
- Manganese alone did not induce tumor necrosis factor alpha (TNF-α) or inducible nitric oxide synthase (iNOS) expression at tested concentrations.
- Manganese potentiated lipopolysaccharide/interferon-gamma-induced iNOS and TNF-α gene expression in glial cells.
- This potentiation was associated with increased free manganese, oxidative stress, mitogen-activated protein kinase activation, and enhanced NF-κB and AP-1 binding activity, partly via IκB-α degradation.
- Manganese decreased iNOS enzymatic activity, which was reversed by tetrahydrobiopterin, suggesting cofactor depletion.
Conclusions:
- Manganese exposure can modulate glial inflammation by enhancing pro-inflammatory responses and affecting nitric oxide production.
- The study highlights complex molecular strategies through which manganese influences neuroinflammation, involving oxidative stress and transcription factor activation.
- Findings suggest manganese's role in neurotoxicity may be mediated through its impact on glial inflammatory pathways.