• Sarah L Dunn, Elizabeth A Young, Matthew D Hall, and Shaun McNulty.
• Pfizer Global Research and Development, Cambridge Laboratories, Cambridge University Forvie Site, Cambridge, UK.

AbstractThe striatum has been implicated as the site of action mediating neurotoxic effects of interleukin-1 (IL-1) during ischemia. However, the molecular mechanisms underlying these events have yet to be fully addressed. In the present study, primary cultures of rat striatal cells were used as a model for the study of IL-1 signaling pathways in the striatum. Immunocytochemical analyses revealed that these cultures consisted of a mixture of neurones and astrocytes and demonstrated expression of the IL-1 type I receptor (IL-1RI) on both cell types. Treatment with IL-1 (3 units/ml) for 10 min increased phosphorylation of p38 MAP kinase in striatal cells. The endogenous IL-1RI inhibitor IL-1Ra (24 ng/ml) and the p38 MAP kinase inhibitor SB203580 (10 nM) both inhibited this response. Analysis of the effects of IL-1 on nuclear translocation of the transcription factor NF-kB revealed that NF-kB became activated in a time-dependent manner. Immunocytochemistry revealed that IL-1 stimulated p38 phosphorylation and NF-kB translocation in astrocytes only. TaqMan real-time quantitative PCR analysis revealed that IL-1 stimulated gene expression of tumor necrosis factor-alpha (TNF) in striatal cultures. The p38 MAP kinase inhibitor SB203580 failed to inhibit the effects of IL-1 on NF-kB translocation or gene transcription. These studies have demonstrated significant aspects of the IL-1 signaling cascade in cultured striatum. Of particular interest is the finding that IL-1 stimulated activation of p38 MAP kinase and NF-kB in striatal astrocytes exclusively.Copyright 2002 Wiley-Liss, Inc.

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