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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.