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α-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1

Title
α-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1
Authors
Lee E.-J.Woo M.-S.Moon P.-G.Baek M.-C.Choi I.-Y.Kim W.-K.Junn E.Kim H.-S.
Ewha Authors
김희선
SCOPUS Author ID
김희선scopus
Issue Date
2010
Journal Title
Journal of Immunology
ISSN
0022-1767JCR Link
Citation
vol. 185, no. 1, pp. 615 - 623
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
The mutation or overexpression of α-synuclein protein plays a pivotal role in the pathogenesis of Parkinson's disease. In our preliminary experiments, we found that α-synuclein induced the expression of matrix metalloproteinases (MMPs) (MMP-1, -3, -8, and -9) in rat primary cultured microglia. Thus, the current study was undertaken to determine the roles of MMPs in α-synuclein - induced microglial activation. The inhibition of MMP-3, -8, or -9 significantly reduced NO and reactive oxygen species levels and suppressed the expression of TNF-α and IL-1β. Notably, MMP-8 inhibitor suppressed TNF-α production more efficaciously than MMP-3 or MMP-9 inhibitors. Inhibition of MMP-3 or -9 also suppressed the activities of MAPK, NF-κB, and AP-1. Previously, protease-activated receptor-1 (PAR-1) has been associated with the actions of MMPs, and thus, we further investigated the role of PAR-1 in α-synuclein-induced inflammatory reactions. A PAR-1-specific inhibitor and a PAR-1 antagonist significantly suppressed cytokine levels, and NO and reactive oxygen species production in α-synuclein-treated microglia. Subsequent PAR-1 cleavage assay revealed that MMP-3, -8, and -9, but not α-synuclein, cleaved the synthetic peptide containing conventional PAR-1 cleavage sites. These results suggest that MMPs secreted by α-synuclein-stimulated microglia activate PAR-1 and amplify microglial inflammatory signals in an autocrine or paracrine manner. Furthermore, our findings suggest that modulation of the activities of MMPs and/or PAR-1 may provide a new therapeutic strategy for Parkinson's disease. Copyright © 2010 by The American Association of Immunologists, Inc.
DOI
10.4049/jimmunol.0903480
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의학전문대학원 > 의학과 > Journal papers
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