Linked Life Data

15814801

Source:http://linkedlifedata.com/resource/pubmed/id/15814801

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2005-4-7
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1529-2401
pubmed:author
pubmed:issnType
Electronic
pubmed:day
6
pubmed:volume
25
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3701-11
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:15814801-Animals, pubmed-meshheading:15814801-Animals, Newborn, pubmed-meshheading:15814801-Apoptosis, pubmed-meshheading:15814801-Blotting, Northern, pubmed-meshheading:15814801-Blotting, Western, pubmed-meshheading:15814801-Brain, pubmed-meshheading:15814801-Cells, Cultured, pubmed-meshheading:15814801-Culture Media, Conditioned, pubmed-meshheading:15814801-Culture Media, Serum-Free, pubmed-meshheading:15814801-Cytokines, pubmed-meshheading:15814801-Drug Interactions, pubmed-meshheading:15814801-Electrophoresis, Gel, Two-Dimensional, pubmed-meshheading:15814801-Enzyme Inhibitors, pubmed-meshheading:15814801-Enzyme-Linked Immunosorbent Assay, pubmed-meshheading:15814801-Gene Expression, pubmed-meshheading:15814801-Humans, pubmed-meshheading:15814801-Lipopolysaccharides, pubmed-meshheading:15814801-Matrix Metalloproteinase 3, pubmed-meshheading:15814801-Mice, pubmed-meshheading:15814801-Microglia, pubmed-meshheading:15814801-Mitogen-Activated Protein Kinases, pubmed-meshheading:15814801-Nerve Degeneration, pubmed-meshheading:15814801-Neurons, pubmed-meshheading:15814801-Rats, pubmed-meshheading:15814801-Signal Transduction, pubmed-meshheading:15814801-Time Factors
pubmed:year
2005
pubmed:articleTitle
Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia.
pubmed:affiliation
Burke Medical Research Institute, Weill Medical College and Graduate School of Medical Sciences of Cornell University, White Plains, New York 10605, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't