Mechanism of plasminogen activator inhibitor-1 regulation by oncostatin M and interleukin-1 in human astrocytes

被引:34
作者
Kasza, A
Kiss, DL
Gopalan, S
Xu, WL
Rydel, RE
Koj, A
Kordula, T [1 ]
机构
[1] Cleveland State Univ, Dept Biol Geol & Environm Sci, Cleveland, OH 44115 USA
[2] Jagiellonian Univ, Inst Mol Biol, Dept Cell Biochem, Krakow, Poland
[3] Elan Pharmaceut, San Francisco, CA USA
关键词
astrocytes; c-fos; inflammation; interleukin-1; oncostatin M; PAI-1;
D O I
10.1046/j.1471-4159.2002.01163.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glial cells that produce and respond to various cytokines mediate inflammatory processes in the brain. Here, we show that oncostatin M (OSM) and interleukin-1 (IL-1) regulate the expression of plasminogen activator inhibitor-1 (PAI-1) and urokinase-type plasminogen activator (uPA) in human astrocytes. Using the PAI-1 reporter constructs we show that the -58 to -51 proximal element mediates activation by both cytokines. This element is already bound by c-fos/c-jun heterodimers in unstimulated astrocytes, and treatment with cytokine strongly stimulates both expression of c-fos and binding of c-fos/c-jun heterodimers. In addition, IL-1 activates an inhibitory mechanism that down-regulates PAI-1 expression after longer exposure to this cytokine. Overexpression of dominant-negative signal transducer and activator of transcription-1 (STAT1), STAT3, STAT5 and inhibitor of nuclear factor-kappaB (IkappaB) suppressed OSM/IL-1-induced expression of the PAI-1 reporter construct. We conclude that OSM and IL-1 regulate the PAI-1 gene expression via up-regulating c-fos levels and subsequent binding of c-fos/c-jun heterodimers to the proximal element of the PAI-1 gene.
引用
收藏
页码:696 / 703
页数:8
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