Message and protein-level elevation of tumor necrosis factor α (TNFα) and TNFα-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis

Kenneth Hensley; Joe Fedynyshyn; Scott Ferrell; Robert A Floyd; Brian Gordon; Paula Grammas; Ladan Hamdheydari; Molina Mhatre; Shenyun Mou; Quentin N Pye; Charles Stewart; Melinda West; Stuart West; Kelly S Williamson

Neurobiology of Disease (Oct 2003)

Message and protein-level elevation of tumor necrosis factor α (TNFα) and TNFα-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis

Kenneth Hensley,
Joe Fedynyshyn,
Scott Ferrell,
Robert A Floyd,
Brian Gordon,
Paula Grammas,
Ladan Hamdheydari,
Molina Mhatre,
Shenyun Mou,
Quentin N Pye,
Charles Stewart,
Melinda West,
Stuart West,
Kelly S Williamson

Affiliations

Kenneth Hensley: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Joe Fedynyshyn: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Scott Ferrell: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Robert A Floyd: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Brian Gordon: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Paula Grammas: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Ladan Hamdheydari: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Molina Mhatre: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Shenyun Mou: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Quentin N Pye: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Charles Stewart: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Melinda West: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Stuart West: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA
Kelly S Williamson: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA; Life Science Group, Bio-Rad Laboratories, 2000 Alfred Noble Drive, Hercules, CA 94547, USA; Laboratory Animal Resource Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA

Journal volume & issue: Vol. 14, no. 1
pp. 74 – 80

Abstract

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Recent data indicate that certain pro-inflammatory cytokines are transcriptionally upregulated in the spinal cords of G93A-SOD1 mice, a model of amyotrophic lateral sclerosis (ALS). We previously showed that the receptor for tumor necrosis factor α (TNF-R1) was notably elevated at late presymptomatic as well as symptomatic phases of disease (J. Neurochem. 82 (2002) 365). We now extend these findings by showing that message for TNFα, as well as mRNA for interferon γ (IFNγ) and transforming growth factor β1/2 (TGFβ1, TGFβ2), is simultaneously increased. Furthermore, TNFα protein is significantly increased in G93A-SOD1 mouse spinal cords, as are protein levels for interleukin-6 (IL6), IFNγ, and the chemokines RANTES (CCL5) and KC. The interaction of TNFα, IL6, and IFNγ proteins was modeled in vitro using Walker EOC-20 murine microglia with nitrite (NO2−) efflux as a quantitative index of cell response. TNFα alone caused robust NO2− flux, while IL6 had a lesser effect and neither IFNγ nor IL1β was active when applied singly. The TNFα stimulus was potently magnified in the presence of IL6 or IFNγ. When applied in combination at very low concentrations, IFNγ co-synergized with IL6 to produce a multiplicative increase in NO2− after stimulation with TNFα. Taken together, these data suggest that modest increases in multiple synergistic cytokines could produce a disproportionately severe activation of microglia within the degenerating spinal cord. Our data support a model wherein TNFα acts as a principal driver for neuroinflammation, while several co-stimulating cytokines and chemokines act to potentiate the TNFα effects.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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