title: Regulation of tissue plasminogen activator/plasminogen activator inhibitor-1 by hydrocortisone in rat primary astrocytes.
abstract: Although originally known as a plasma serine protease involved in clot dissolution, tPA and its primary inhibitor, PAI-1, play crucial roles in synaptic reorganization and plasticity in the central nervous system. In contrast to the wide array of work conducted in neural cells, relatively little is known about the regulatory mechanism governing tPA/PAI-1 expression in astrocytes. Glucocorticoids (GCs) such as hydrocortisone regulate the expression of tPA/PAI-1 in various biological systems in a tissue-specific manner. However, little is known about GC-mediated regulation of tPA/PAI-1 system in CNS. The aims of the present study were to investigate whether tPA/PAI-1 expression is regulated by hydrocortisone in rat primary astrocytes. Enzyme activity of tPA was decreased in a concentration-dependent manner by hydrocortisone treatment, and the activity of PAI-1 was increased by hydrocortisone. Hydrocortisone did not affect the level of tPA mRNA, which suggests that transcriptional down-regulation of tPA mRNA is not involved in the down-regulation of tPA enzyme activity in astrocytes. However, the level of PAI-1 mRNA and protein was increased. Both hydrocortisone and a tPA-Stop treatment prevented glutamate-induced neurotoxicity in rat cortical primary mixed astrocyte-neuron culture, which suggests a neurotoxic role for tPA in our culture system. Interestingly, hydrocortisone further increased LPS-induced up-regulation of PAI-1 while inhibiting the up-regulation of iNOS and COX-2 expression. Our data show that hydrocortisone up-regulated PAI-1 expression along with down-regulation of tPA activity in both normal and inflammatory conditions.
authors.affiliation: Department of Neurology and Institute of Biomedical Science and Technology, Konkuk University, Seoul, Korea.
authors.forename: Kyoung Ja
authors.initials: KJ
authors.lastname: Kwon
authors.forename: Kyu Suk
authors.initials: KS
authors.lastname: Cho
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Jung Nam
authors.initials: JN
authors.lastname: Kim
authors.forename: So Hyun
authors.initials: SH
authors.lastname: Joo
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Ryu
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
authors.forename: Seol-Heui
authors.initials: SH
authors.lastname: Han
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000633:toxicity; D006854:Hydrocortisone / Q000502:physiology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D009498:Neurotoxins; D017395:Plasminogen Activator Inhibitor 1; D018698:Glutamic Acid; D010959:Tissue Plasminogen Activator; D006854:Hydrocortisone