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Retinoids and activation of PKC induce tissue-type plasminogen activator expression and storage in human astrocytes.

Journal article
Authors Karin Hultman
Anna Tjärnlund-Wolf
R J Fish
Ulrika Wilhelmsson
Bertil Rydenhag
Milos Pekny
E K O Kruithof
Christina Jern
Published in Journal of thrombosis and haemostasis : JTH
Volume 6
Issue 10
Pages 1796-803
ISSN 1538-7836
Publication year 2008
Published at Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
Pages 1796-803
Language en
Subject categories Experimental brain research, Molecular neurobiology, Neurobiology


BACKGROUND: Emerging data demonstrate important roles for tissue-type plasminogen activator (t-PA) in the central nervous system (CNS). In contrast to endothelial cells, little is known about the regulation of t-PA gene expression and secretion in astrocytes. OBJECTIVES: The aims of the present study were to investigate whether t-PA gene expression is regulated by retinoids and the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) in human astrocytes, and to study whether t-PA is stored and subject to regulated release from these cells, as with endothelial cells. METHODS: Native human astrocytes were treated with RA and/or PMA. mRNA was quantified by real-time RT-PCR and protein secretion determined by ELISA. Intracellular t-PA immunoreactivity in astrocytes was examined by immunocyto- and histochemistry. RESULTS: RA and/or PMA induced a time-dependent increase in t-PA mRNA and protein levels in astrocytes, reaching 10-fold after combined treatment. This was associated with increased amounts of t-PA storage in intracellular granular structures. Both forskolin and histamine induced regulated release of t-PA. The presence of t-PA in reactive astrocytes was confirmed in human brain tissue. CONCLUSIONS: These data show that RA and PKC activation induce a strong up-regulation of t-PA expression in astrocytes, and increased intracellular storage pools. Moreover, a regulated release of t-PA can be induced from these cells. This raises the possibility that astrocytes contribute to the regulation of extracellular t-PA levels in the CNS.

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