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Expression of Plasminogen Activator Inhibitor-1 and Protease Nexin-1 in Human Astrocytes: Response to Injury-Related Factors.

Journal article
Authors Karin Hultman
Fredrik Blomstrand
Michael Nilsson
Ulrika Wilhelmsson
Kristina Malmgren
Milos Pekny
Tina Kousted
Christina Jern
Anna Tjärnlund-Wolf
Published in Journal of Neuroscience Research
Volume 88
Issue 11
Pages 2441-2449
ISSN 1097-4547
Publication year 2010
Published at Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
Pages 2441-2449
Language en
Links dx.doi.org/10.1002/jnr.22412
https://gup.ub.gu.se/file/86216
Keywords Amyloid beta-Protein Precursor, biosynthesis, Astrocytes, metabolism, Brain Chemistry, Brain Injuries, metabolism, pathology, Cell Hypoxia, Cells, Cultured, Cytokines, biosynthesis, Enzyme-Linked Immunosorbent Assay, Gene Expression, physiology, Glial Fibrillary Acidic Protein, biosynthesis, genetics, Humans, Hypoxia, Brain, pathology, Immunohistochemistry, Plasminogen Activator Inhibitor 1, biosynthesis, Protease Nexins, RNA, Messenger, biosynthesis, genetics, Receptors, Cell Surface, biosynthesis, Serpin E2, Serpins, biosynthesis, Tumor Necrosis Factor-alpha, metabolism
Subject categories Physiology

Abstract

Astrocytes play a diverse role in central nervous system (CNS) injury. Production of the serine protease inhibitors (serpins) plasminogen activator inhibitor-1 (PAI-1) and protease nexin-1 (PN-1) by astrocytes may counterbalance excessive serine protease activity associated with CNS pathologies such as ischemic stroke. Knowledge regarding the regulation of these genes in the brain is limited, so the objective of the present study was to characterize the effects of injury-related factors on serpin expression in human astrocytes. Native human astrocytes were exposed to hypoxia or cytokines, including interleukin-6 (IL-6), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), IL-10, transforming growth factor-alpha (TGF-alpha), and TGF-beta for 0-20 hr. Serpin mRNA expression and protein secretion were determined by real-time RT-PCR and ELISA, respectively. Localization of PAI-1 and PN-1 in human brain tissue was examined by immunohistochemistry. Hypoxia and all assayed cytokines induced a significant increase in PAI-1 expression, whereas prolonged treatment with IL-1beta or TNF-alpha resulted in a significant down-regulation. The most pronounced induction of both PAI-1 and PN-1 was observed following early treatment with TGF-alpha. In contrast to PAI-1, the PN-1 gene did not respond to hypoxia. Positive immunoreactivity for PAI-1 in human brain tissue was demonstrated in reactive astrocytes within gliotic areas of temporal cortex. We show here that human astrocytes express PAI-1 and PN-1 and demonstrate that this astrocytic expression is regulated in a dynamic manner by injury-related factors.

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