Interferon-gamma-dependent cytotoxic activation of human astrocytes and astrocytoma cells.
Identifieur interne : 001E31 ( Main/Exploration ); précédent : 001E30; suivant : 001E32Interferon-gamma-dependent cytotoxic activation of human astrocytes and astrocytoma cells.
Auteurs : Sadayuki Hashioka ; Andis Klegeris ; Claudia Schwab ; Patrick L. McgeerSource :
- Neurobiology of aging [ 1558-1497 ] ; 2009.
English descriptors
- KwdEn :
- Alzheimer Disease (metabolism), Amyotrophic Lateral Sclerosis (metabolism), Astrocytes (immunology), Astrocytes (physiology), Astrocytoma (immunology), Astrocytoma (physiopathology), Brain (immunology), Brain (physiopathology), Cell Line, Tumor, Cell Survival, Humans, Interferon-gamma (metabolism), Janus Kinases (antagonists & inhibitors), Janus Kinases (metabolism), Lipopolysaccharides (metabolism), Multiple Sclerosis (metabolism), Parkinson Disease (metabolism), Receptors, Interferon (metabolism), Signal Transduction, Tumor Necrosis Factor-alpha (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Janus Kinases.
- chemical , metabolism : Interferon-gamma, Janus Kinases, Lipopolysaccharides, Receptors, Interferon, Tumor Necrosis Factor-alpha.
- immunology : Astrocytes, Astrocytoma, Brain.
- metabolism : Alzheimer Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Parkinson Disease.
- physiology : Astrocytes.
- physiopathology : Astrocytoma, Brain.
- Cell Line, Tumor, Cell Survival, Humans, Signal Transduction.
Abstract
Astrocytes and microglia become activated in a broad spectrum of inflammatory neurodegenerative diseases. Activated microglia are widely believed to be the principal source of inflammation-induced neuronal degeneration in these disorders. To investigate the neurotoxic potential of human astrocytes, we exposed them and human astrocytic U-373 MG cells to a variety of inflammatory stimulants. We then assessed the effects of their supernatants on human SH-SY5 cells. When astrocytes and U-373 MG cells were stimulated with interferon (IFN)-gamma (150U/ml), their supernatants significantly reduced SH-SY5Y cell viability. Other powerful inflammatory stimulants such as lipopolysaccharide (0.5mug/ml), tumor necrosis factor-alpha (10ng/ml) and interleukin-1beta (10ng/ml), alone or in combination, were without effect. These combinations were also unable to enhance the IFN-gamma effect. The induced cytotoxicities were reversed by JAK inhibitor I, a potent and specific inhibitor of JAKs. This result indicates that the neurotoxic effect was proceeding through the IFN-gamma receptor (IFNGR)-JAK-STAT intracellular pathway. To establish that the IFNGR is expressed on both cultured astrocytes and U-373 MG cells, we performed RT-PCR on total RNA extracts to identify a specific IFNGR product. We showed the protein product on these cultured cells by immunocytochemistry using an antibody to IFNGR. Finally, using human postmortem material, we showed sharp upregulation of the IFNGR on activated astrocytes in affected areas in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. These findings suggest that activated astrocytes may become neurotoxic when stimulated by IFN-gamma and may therefore exacerbate the pathology in a spectrum of neurodegenerative diseases.
DOI: 10.1016/j.neurobiolaging.2008.02.019
PubMed: 18375019
Affiliations:
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Le document en format XML
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<author><name sortKey="Schwab, Claudia" sort="Schwab, Claudia" uniqKey="Schwab C" first="Claudia" last="Schwab">Claudia Schwab</name>
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<author><name sortKey="Mcgeer, Patrick L" sort="Mcgeer, Patrick L" uniqKey="Mcgeer P" first="Patrick L" last="Mcgeer">Patrick L. Mcgeer</name>
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<series><title level="j">Neurobiology of aging</title>
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<term>Astrocytoma (immunology)</term>
<term>Astrocytoma (physiopathology)</term>
<term>Brain (immunology)</term>
<term>Brain (physiopathology)</term>
<term>Cell Line, Tumor</term>
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<term>Humans</term>
<term>Interferon-gamma (metabolism)</term>
<term>Janus Kinases (antagonists & inhibitors)</term>
<term>Janus Kinases (metabolism)</term>
<term>Lipopolysaccharides (metabolism)</term>
<term>Multiple Sclerosis (metabolism)</term>
<term>Parkinson Disease (metabolism)</term>
<term>Receptors, Interferon (metabolism)</term>
<term>Signal Transduction</term>
<term>Tumor Necrosis Factor-alpha (metabolism)</term>
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<term>Janus Kinases</term>
<term>Lipopolysaccharides</term>
<term>Receptors, Interferon</term>
<term>Tumor Necrosis Factor-alpha</term>
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<term>Astrocytoma</term>
<term>Brain</term>
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<term>Amyotrophic Lateral Sclerosis</term>
<term>Multiple Sclerosis</term>
<term>Parkinson Disease</term>
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<term>Brain</term>
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<term>Cell Survival</term>
<term>Humans</term>
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<front><div type="abstract" xml:lang="en">Astrocytes and microglia become activated in a broad spectrum of inflammatory neurodegenerative diseases. Activated microglia are widely believed to be the principal source of inflammation-induced neuronal degeneration in these disorders. To investigate the neurotoxic potential of human astrocytes, we exposed them and human astrocytic U-373 MG cells to a variety of inflammatory stimulants. We then assessed the effects of their supernatants on human SH-SY5 cells. When astrocytes and U-373 MG cells were stimulated with interferon (IFN)-gamma (150U/ml), their supernatants significantly reduced SH-SY5Y cell viability. Other powerful inflammatory stimulants such as lipopolysaccharide (0.5mug/ml), tumor necrosis factor-alpha (10ng/ml) and interleukin-1beta (10ng/ml), alone or in combination, were without effect. These combinations were also unable to enhance the IFN-gamma effect. The induced cytotoxicities were reversed by JAK inhibitor I, a potent and specific inhibitor of JAKs. This result indicates that the neurotoxic effect was proceeding through the IFN-gamma receptor (IFNGR)-JAK-STAT intracellular pathway. To establish that the IFNGR is expressed on both cultured astrocytes and U-373 MG cells, we performed RT-PCR on total RNA extracts to identify a specific IFNGR product. We showed the protein product on these cultured cells by immunocytochemistry using an antibody to IFNGR. Finally, using human postmortem material, we showed sharp upregulation of the IFNGR on activated astrocytes in affected areas in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. These findings suggest that activated astrocytes may become neurotoxic when stimulated by IFN-gamma and may therefore exacerbate the pathology in a spectrum of neurodegenerative diseases.</div>
</front>
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<tree><noCountry><name sortKey="Hashioka, Sadayuki" sort="Hashioka, Sadayuki" uniqKey="Hashioka S" first="Sadayuki" last="Hashioka">Sadayuki Hashioka</name>
<name sortKey="Klegeris, Andis" sort="Klegeris, Andis" uniqKey="Klegeris A" first="Andis" last="Klegeris">Andis Klegeris</name>
<name sortKey="Mcgeer, Patrick L" sort="Mcgeer, Patrick L" uniqKey="Mcgeer P" first="Patrick L" last="Mcgeer">Patrick L. Mcgeer</name>
<name sortKey="Schwab, Claudia" sort="Schwab, Claudia" uniqKey="Schwab C" first="Claudia" last="Schwab">Claudia Schwab</name>
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