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

被引:181
作者
Hensley, K
Fedynyshyn, J
Ferrell, S
Floyd, RA
Gordon, B
Grammas, P
Hamdheydari, L
Mhatre, M
Mou, S
Pye, QN
Stewart, C
West, M
West, S
Williamson, KS
机构
[1] Oklahoma Med Res Fdn, Free Rad Biol & Aging Res Program, Oklahoma City, OK 73104 USA
[2] Univ Oklahoma, Ctr Hlth Sci, Ctr Neurosci, Oklahoma City, OK 73104 USA
[3] Life Sci Grp, Bio Rad Labs, Hercules, CA 94547 USA
[4] Oklahoma Med Res Fdn, Lab Anim Resource Ctr, Oklahoma City, OK 73104 USA
[5] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73190 USA
关键词
microglia; amyotrophic lateral sclerosis; neuroinflammation; tumor necrosis factor; cytokines; chemokines;
D O I
10.1016/S0969-9961(03)00087-1
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 alpha (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 TNFalpha, as well as mRNA for interferon gamma (IFNgamma) and transforming growth factor beta1/2 (TGFbeta1, TGFbeta2), is simultaneously increased. Furthermore, TNFalpha protein is significantly increased in G93A-SOD1 mouse spinal cords, as are protein levels for interleukin-6 (IL6), IFNgamma, and the chemokines RANTES (CCL5) and KC. The interaction of TNFalpha, IL6, and IFNgamma proteins was modeled in vitro using Walker EOC-20 murine microglia with nitrite (NO2-) efflux as a quantitative index of cell response. TNFalpha alone caused robust NO2- flux, while IL6 had a lesser effect and neither IFNgamma nor IL1beta was active when applied singly. The TNFalpha stimulus was potently magnified in the presence of IL6 or IFNgamma. When applied in combination at very low concentrations, IFNgamma co-synergized with IL6 to produce a multiplicative increase in NO2- after stimulation with TNFalpha. 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 TNFalpha acts as a principal driver for neuroinflammation, while several co-stimulating cytokines and chemokines act to potentiate the TNFalpha effects. (C) 2003 Elsevier Science (USA). All rights reserved.
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页码:74 / 80
页数:7
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