Activation of microglia reveals a non-proteolytic cytokine function for tissue plasminogen activator in the central nervous system.
Tissue plasminogen activator mediates excitotoxin-induced neurodegeneration and microglial activation in the mouse hippocampus. Here we show that tissue plasminogen activator (tPA) acts in a protease-independent manner to modulate the activation of microglia, the cells of the central nervous system with macrophage properties. Cultured microglia from tPA-deficient mice can phagocytose as efficiently as wild-type microglia. However, tPA-deficient microglia in mixed cortical cultures exhibit attenuated activation in response to lipopolysaccharide, as judged by morphological changes, increased expression of the activation marker F4/80 and the release of the pro-inflammatory cytokine tumor necrosis factor-(&agr;). When tPA is added to tPA deficient cortical cultures prior to endotoxin stimulation, microglial activation is restored to levels comparable to that observed in wild-type cells. Proteolytically-inactive tPA can also restore activation of tPA-deficient microglia in culture and in vivo. However, this inactive enzyme does not restore susceptibility of tPA-deficient hippocampal neurons to excitotoxin-mediated cell death. These results dissociate two different functions of tPA: inactive enzyme can mediate microglial activation, whereas proteolytically-competent protein also promotes neuronal degeneration. Thus tPA is identified as a new cytokine in the central nervous system.
Rogove
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AD
Program in Pharmacology, MSTP Program, Department of Psychiatry, University Medical Center at Stony Brook, Stony Brook, NY 11794-8101, USA.
Siao
C
C
Keyt
B
B
Strickland
S
S
Tsirka
S E
SE
D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis; D002384:Catalysis; D002478:Cells, Cultured; D002490:Central Nervous System / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006868:Hydrolysis; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity; D010587:Phagocytosis; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D000943:Antigens, Differentiation; D016207:Cytokines; D008070:Lipopolysaccharides; D009498:Neurotoxins; D016211:Transforming Growth Factor alpha; C036763:monocyte-macrophage differentiation antigen; D010959:Tissue Plasminogen Activator