The effect of gp130 stimulation on glutamate-induced excitotoxicity in primary hippocampal neurons.

Primary hippocampal neurons from newborn rats treated with glutamate showed clear excitotoxicity. This excitotoxicity could be reversed by treatment of the cells with cytokines of the interleukin-6 family. Stimulation of gp130 on hippocampal neurons resulted in tyrosine phosphorylation of STAT3 and activation of p42 and p44 MAP kinases. Receptors for the interleukin-6 type cytokines are active in membrane bound and soluble form. To address the question whether the neurotrophic effect of interleukin-6 type cytokines requires soluble cytokine receptors we used fusion proteins of interleukin-6 coupled to the soluble interleukin-6 receptor and ciliary neurotrophic factor coupled to the soluble ciliary neurotrophic factor receptor. Ciliary neurotrophic factor was as active as the cytokine-receptor fusion protein, indicating that hippocampal neurons express ciliary neurotrophic factor receptor on the cell surface. In contrast, interleukin-6 was only active at very high concentrations whereas the fusion protein of interleukin-6 coupled to the soluble interleukin-6 receptor (Hyper-IL-6) exhibited high neurotrophic activity at the same concentrations as ciliary neurotrophic factor. These data indicate that interleukin-6 receptor expression is very low on hippocampal neurons and that gp130 stimulation can be used to rescue hippocampal neurons from excitotoxicity.