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Matrix Metalloproteinase-3: A Novel Signaling Proteinase from Apoptotic Neuronal Cells That Activates Microglia

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Author(s)
Yoon Seong KimSung Soo KimJeong Je ChoDong Hee ChoiOnyou HwangDong Hoon ShinHong Sung ChunM. Flint BealTong H. Joh
Keimyung Author(s)
Shin, Dong Hoon
Department
Dept. of Preventive Medicine (예방의학)
Journal Title
Journal of Neuroscience
Issued Date
2005
Volume
25
Issue
14
Keyword
microgliaapoptosisneurodegenerationcytokinesmatrix metalloproteinase-3MMP-3
Abstract
Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative human brain disorders.
We sought to investigate molecular signaling mechanisms that govern activation of microglia in apoptotic neuronal degeneration.
We report here that the active form of matrix metalloproteinase-3 (MMP-3) was released into the serum-deprived media (SDM) of PC12
cells and other media of apoptotic neuronal cells within 2– 6 h of treatment of the cells, and SDM and catalytic domain of recombinant
MMP-3 (cMMP-3) activated microglia in primary microglia cultures as well as BV2 cells, a mouse microglia cell line. Both SDM and
cMMP-3 induced generation of tumor necrosis factor (TNF- ), interleukin-6 (IL-6), IL-1 , and interleukin-1 receptor antagonist but
not IL-12 and inducible nitric oxide synthase, which are readily induced by lipopolysaccharide, in microglia, suggesting that there is a
characteristic pattern of microglial cytokine induction by apoptotic neurons. Neither glial cell line-derived neurotrophic factor nor
anti-inflammatory cytokines, such as IL-10 and transforming growth factor- 1, were induced. SDM and cMMP-3 extensively released
TNF- from microglia and activated the nuclear factor- B pathway, and these microglial responses were totally abolished by preincubation
with an MMP-3 inhibitor, NNGH [N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid]. MMP-3-mediated microglial
activation mostly depended on ERK (extracellular signal-regulated kinase) phosphorylation but not much on either JNK (c-Jun
N-terminal protein kinase) or p38 activation. Conditioned medium of SDM- or cMMP-3-activated BV2 cells caused apoptosis of PC12
cells. These results strongly suggest that the distinctive signal of neuronal apoptosis is the release of active form of MMP-3 that activates
microglia and subsequently exacerbates neuronal degeneration. Therefore, the release of MMP-3 from apoptotic neurons may play a
major role in degenerative human brain disorders, such as Parkinson’s disease.
Key words: microglia; apoptosis; neurodegeneration; cytokines; matrix metalloproteinase-3; MMP-3
Keimyung Author(s)(Kor)
신동훈
Publisher
School of Medicine
Citation
Yoon Seong Kim et al. (2005). Matrix Metalloproteinase-3: A Novel Signaling Proteinase from Apoptotic Neuronal Cells That Activates Microglia. Journal of Neuroscience, 25(14), 3701–3711. doi: 10.1523/JNEUROSCI.4346-04.2005
Type
Article
ISSN
0270-6474
DOI
10.1523/JNEUROSCI.4346-04.2005
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/34508
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Preventive Medicine (예방의학)
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