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Metalloproteinases are enriched in microglia compared with leukocytes and they regulate cytokine levels in activated microglia
- Source :
- Glia. 55:516-526
- Publication Year :
- 2007
- Publisher :
- Wiley, 2007.
-
Abstract
- Microglia are resident immune cells within the central nervous system (CNS). They become activated following neurological insults and increase their expression of cytokines. Also elevated in CNS injuries are proteases, including matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs). The spectrum of metalloproteinase members expressed by microglia and by the systemic leukocytes that infiltrate the injured CNS is unknown, as are their functions. We determined the levels of transcripts encoding all 24 MMPs, nine ADAMs, and their four physiological antagonists, tissue inhibitor of metalloproteinases (TIMPs), in human microglia, B and T cells, monocytes, and neutrophils. We found a distinct pattern for each immune subset and an enrichment of metalloproteinases in microglia compared with leukocytes. When microglia were activated, there was an upregulation of transcripts for nine metalloproteinases, and reduction of TIMP3. Activation of microglia also resulted in increased levels of tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-10 protein in the conditioned media of cells. The amount of secreted TNF-a ,b ut not IL-1b or IL-10, was suppressed by BB94, a broad spectrum metalloproteinase inhibitor, and by TIMP3 but not TIMP1 or TIMP2. This inhibitory profile suggests the involvement of an ADAM member in TNF-a secretion. We conclude that microglia bear a metalloproteinase signature distinct from systemic cells, and that following activation, microglia upregulate TNF-a protein levels through a combination of elevated cytokine transcripts, increased metalloproteinase level and activity, and through the decrease of TIMP3. The results have implications for the regulation of neuroinflammation and its outcomes following CNS injuries. V C 2007 Wiley-Liss, Inc.
- Subjects :
- Adult
Central Nervous System
Lipopolysaccharides
medicine.medical_treatment
Interleukin-1beta
Biology
Matrix metalloproteinase
Cellular and Molecular Neuroscience
Leukocytes
medicine
Humans
RNA, Messenger
Cells, Cultured
Neuroinflammation
TIMP1
Inflammation
Microglia
Tumor Necrosis Factor-alpha
Interleukin
Interleukin-10
Up-Regulation
ADAM Proteins
medicine.anatomical_structure
Cytokine
Neurology
Immunology
Metalloproteases
Cancer research
Cytokines
RNA
Tumor necrosis factor alpha
Cell activation
Subjects
Details
- ISSN :
- 10981136 and 08941491
- Volume :
- 55
- Database :
- OpenAIRE
- Journal :
- Glia
- Accession number :
- edsair.doi.dedup.....aaae260e0c81020685d4e15d5c52e390