Profound increase in sensitivity to glutamatergic‐ but not cholinergic agonist‐induced seizures in transgenic mice with astrocyte production of IL‐6

Abstract

Transgenic mice with glial fibrillary acidic protein (GFAP) promoter driven-astrocyte production of the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) were used to determine whether the pre-existing production of these cytokines in vivo might modulate the sensitivity of neurons to excitotoxic agents. Low doses of kainic acid (5 mg/kg) that produced little or no behavioral or electroencephalogram (EEG) alterations in wild type or glial fibrillary acidic protein (GFAP)-TNF animals induced severe tonic-clonic seizures and death in GFAP-IL6 transgenic mice of 2 or 6 months of age. GFAP-IL6 mice were also significantly more sensitive to N-methyl-D-aspartate (NMDA)- but not pilocarpine-induced seizures. Kainic acid uptake in the brain of the GFAP-IL6 mice was higher in the cerebellum but not in other regions. Kainic acid binding in the brain of GFAP-IL6 mice had a similar distribution and density as wild type controls. In the hippocampus of GFAP-IL6 mice that survived low dose kainic acid, there was no change in the extent of either neurodegeneration or astrocytosis. Immunostaining revealed degenerative changes in gamma aminobutyric acid (GABA)- and parvalbumin-positive neurons in the hippocampus of 2-month-old GFAP-IL6 mice which progressed to the loss of these cells at 6 months of age. Thus, GFAP-IL6 but not GFAP-TNF mice showed markedly enhanced sensitivity to glutamatergic- but not cholinergic-induced seizures and lethality. This may relate, in part, to a compromise of inhibitory interneuron function. Therefore, pre-existing IL-6 production and inflammation in the central nervous system (CNS) not only causes spontaneous neurodegeneration but also synergizes with other neurotoxic insults to induce more severe acute functional neurological impairment.

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

“…This might be different when IL-6 is chronically elevated. Increased neuronal death has been described after chronic treatment with IL-6 in vitro and animals with chronic IL-6 expression in astrocytes show enhanced neurodegeneration and increased sensitivity to kainite-induced seizures (Qiu et al, 1998;Nelson et al, 2004;Conroy et al, 2004;Campbell et al, 1993;Samland et al, 2003). It is not yet clear whether adenosine A 1 receptor expression is affected by chronic elevated IL-6 levels.…”

Differential Outcome of Tolerance Induction in Naive versus Activated Theiler's Virus Epitope-Specific CD8+Cytotoxic T Cells

“…It is well recognized that TCR cross-linking, e.g., with anti-CD3 monoclonal antibody, can induce a cytokine release syndrome, leading to significant morbidity and mortality (11,13) due to the release of proinflammatory cytokines, including IL-1, IL-6, and TNF-␣, which can induce fever and seizure responses in mice (7,30,35). We hypothesized that encounter of a high frequency of activated CD8 ϩ T cells with syngeneic cells coupled with a specific antigen (VP2 121-130 ) leads to release of high levels of inflammatory cytokines, resulting in cytokine-induced fever and seizure responses.…”

Acid Sphingomyelinase Deficiency Increases Susceptibility to Fatal Alphavirus Encephalomyelitis

“…Levels of IL-6, a cytokine produced by astrocytes, microglia, and neurons within the CNS (12,21), were higher in the brains of ASM-KO mice than in the brains of WT and Het mice 3 days after infection. Overexpression of IL-6 by astrocytes results in enhanced sensitivity to glutamatergic-induced seizures and death (52). IL-6 is also upregulated in Alzheimer's disease, Parkinson's disease, strokes, encephalitis, and human immunodeficiency virus-associated dementia (2, 21, 52), suggesting a possible role in increased susceptibility of ASM-KO mice to SV infection.…”