TGF-beta1 represses activation and resultant death of microglia via inhibition of phosphatidylinositol 3-kinase activity

Overactivation of microglial cells may cause severe brain tissue damage in various neurodegenerative diseases. Therefore, the overactivation of microglia should be repressed by any means. The present study investigated the potential mechanism and signaling pathway for the repressive effect of TGF-be...

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Published in:The Journal of immunology (1950) 2004-06, Vol.172 (11), p.7015-7023
Main Authors: Kim, Won-Ki, Hwang, So-Young, Oh, Eok-Soo, Piao, Hua Zi, Kim, Ki-Wan, Han, Inn-Oc
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Caspase 3
Caspases - metabolism
Cells, Cultured
Chromones - pharmacology
Cytokines - biosynthesis
Enzyme Activation - drug effects
Lipopolysaccharides - pharmacology
Mice
Microglia - drug effects
Microglia - pathology
Morpholines - pharmacology
Neuroprotective Agents - pharmacology
NF-kappa B - physiology
Nitric Oxide - biosynthesis
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Signal Transduction
Transforming Growth Factor beta - pharmacology
Transforming Growth Factor beta1
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Summary:Overactivation of microglial cells may cause severe brain tissue damage in various neurodegenerative diseases. Therefore, the overactivation of microglia should be repressed by any means. The present study investigated the potential mechanism and signaling pathway for the repressive effect of TGF-beta1, a major anti-inflammatory cytokine, on overactivation and resultant death of microglial cells. A bacterial endotoxin LPS stimulated expression of inducible NO synthase (iNOS) and caused death in cultured microglial cells. TGF-beta1 markedly blocked these LPS effects. However, the LPS-evoked death of microglial cells was not solely attributed to excess production of NO. Because phosphatidylinositol 3-kinase (PI3K) was previously shown to play a crucial role in iNOS expression and cell survival signals, we further studied whether PI3K signaling was associated with the suppressive effect of TGF-beta1. Like TGF-beta1, the PI3K inhibitor LY294002 blocked iNOS expression and death in cultured microglial cells. Both TGF-beta1 and LY294002 decreased the activation of caspases 3 and 11 and the mRNA expression of various kinds of inflammatory molecules caused by LPS. TGF-beta1 was further found to decrease LPS-induced activation of PI3K and Akt. TGF-beta1 and LY294002 suppressed LPS-induced p38 mitogen-activated kinase and c-Jun N-terminal kinase activity. In contrast, TGF-beta1 and LY294002 enhanced LPS-induced NF-kappaB activity. Our data indicate that TGF-beta1 protect normal or damaged brain tissue by repressing overactivation of microglial cells via inhibition of PI3K and its downstream signaling molecules.
ISSN:0022-1767