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-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.
Kim
Won-Ki
WK
Department of Pharmacology, College of Medicine, Division of Molecular Life Sciences and Center for Cell Signalling Research, Ewha Womans University, Seoul, Korea.
Hwang
So-Young
SY
Oh
Eok-Soo
ES
Piao
Hua Zi
HZ
Kim
Ki-Wan
KW
Han
Inn-Oc
IO
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D002867:Chromones; D016207:Cytokines; D008070:Lipopolysaccharides; D009025:Morpholines; D016328:NF-kappa B; D018696:Neuroprotective Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases