PMID- 15814801
OWN - NLM
STAT- MEDLINE
DCOM- 20060301
LR  - 20200225
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 25
IP  - 14
DP  - 2005 Apr 6
TI  - Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal 
      cells that activates microglia.
PG  - 3701-11
AB  - 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 alpha (TNF-alpha), interleukin-6 (IL-6), IL-1beta, 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-beta1, were induced. SDM 
      and cMMP-3 extensively released TNF-alpha from microglia and activated the 
      nuclear factor-kappaB 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.
FAU - Kim, Yoon Seong
AU  - Kim YS
AD  - Burke Medical Research Institute, Weill Medical College and Graduate School of 
      Medical Sciences of Cornell University, White Plains, New York 10605, USA.
FAU - Kim, Sung Soo
AU  - Kim SS
FAU - Cho, Jeong Je
AU  - Cho JJ
FAU - Choi, Dong Hee
AU  - Choi DH
FAU - Hwang, Onyou
AU  - Hwang O
FAU - Shin, Dong Hoon
AU  - Shin DH
FAU - Chun, Hong Sung
AU  - Chun HS
FAU - Beal, M Flint
AU  - Beal MF
FAU - Joh, Tong H
AU  - Joh TH
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Culture Media, Serum-Free)
RN  - 0 (Cytokines)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Lipopolysaccharides)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Apoptosis/drug effects/*physiology
MH  - Blotting, Northern/methods
MH  - Blotting, Western/methods
MH  - Brain/cytology
MH  - Cells, Cultured
MH  - Culture Media, Conditioned/pharmacology
MH  - Culture Media, Serum-Free/pharmacology
MH  - Cytokines/genetics/metabolism
MH  - Drug Interactions
MH  - Electrophoresis, Gel, Two-Dimensional/methods
MH  - Enzyme Inhibitors/pharmacology
MH  - Enzyme-Linked Immunosorbent Assay/methods
MH  - Gene Expression/drug effects
MH  - Humans
MH  - Lipopolysaccharides/toxicity
MH  - Matrix Metalloproteinase 3/chemistry/*metabolism/pharmacology
MH  - Mice
MH  - Microglia/drug effects/*physiology
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Nerve Degeneration/chemically induced/metabolism
MH  - Neurons/*enzymology
MH  - Rats
MH  - Signal Transduction/*physiology
MH  - Time Factors
PMC - PMC6725382
EDAT- 2005/04/09 09:00
MHDA- 2006/03/02 09:00
PMCR- 2005/10/06
CRDT- 2005/04/09 09:00
PHST- 2005/04/09 09:00 [pubmed]
PHST- 2006/03/02 09:00 [medline]
PHST- 2005/04/09 09:00 [entrez]
PHST- 2005/10/06 00:00 [pmc-release]
AID - 25/14/3701 [pii]
AID - 10.1523/JNEUROSCI.4346-04.2005 [doi]
PST - ppublish
SO  - J Neurosci. 2005 Apr 6;25(14):3701-11. doi: 10.1523/JNEUROSCI.4346-04.2005.