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Interferon-γ-dependent cytotoxic activation of human astrocytes and astrocytoma cells

Identifieur interne : 002090 ( Main/Exploration ); précédent : 002089; suivant : 002091

Interferon-γ-dependent cytotoxic activation of human astrocytes and astrocytoma cells

Auteurs : Sadayuki Hashioka [Canada] ; Andis Klegeris [Canada] ; Claudia Schwab [Canada] ; Patrick L. Mcgeer [Canada]

Source :

Neurobiology of aging [ 0197-4580 ] ; 2009.

RBID : Pascal:11-0160724

Descripteurs français

Pascal (Inist)
- Interféron gamma, Astrocyte, Récepteur biologique, Cytotoxicité, Sénescence, Maladie dégénérative, Homme.
Wicri :
- topic : Homme.

English descriptors

KwdEn :
- Astrocyte, Biological receptor, Cytotoxicity, Degenerative disease, Gamma interferon, Human, Senescence.

Abstract

Astrocytes and microglia become activated in abroad 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)-γ (150 U/ml), their supernatants significantly reduced SH-SY5Y cell viability. Other powerful inflammatory stimulants such as lipopolysaccharide (0.5 μg/ml), tumor necrosis factor-α (10ng/ml) and interleukin-1β (lOng/ml), alone or in combination, were without effect. These combinations were also unable to enhance the IFN-γ 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-γ 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-γ and may therefore exacerbate the pathology in a spectrum of neurodegenerative diseases.

Affiliations:

Canada

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Le document en format XML

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<front><div type="abstract" xml:lang="en">Astrocytes and microglia become activated in abroad 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)-γ (150 U/ml), their supernatants significantly reduced SH-SY5Y cell viability. Other powerful inflammatory stimulants such as lipopolysaccharide (0.5 μg/ml), tumor necrosis factor-α (10ng/ml) and interleukin-1β (lOng/ml), alone or in combination, were without effect. These combinations were also unable to enhance the IFN-γ 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-γ 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-γ and may therefore exacerbate the pathology in a spectrum of neurodegenerative diseases.</div>
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Interferon-γ-dependent cytotoxic activation of human astrocytes and astrocytoma cells

Interferon-γ-dependent cytotoxic activation of human astrocytes and astrocytoma cells

Source :

Descripteurs français

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri