Differential effects of interleukin-1beta on neurotoxicity, cytokine induction and glial reaction in specific brain regions.

ABSTRACT

An appropriate inflammatory response is crucial for the maintenance of tissue homeostasis. The inflammatory responses seen in the brain parenchyma differ from those elicited in the periphery, ventricles and meninges. However, although an inflammatory component has been associated with many CNS diseases, the differences among parenchymal inflammatory responses in different brain regions have not yet been fully elucidated. Here, we performed a systematic comparison of the effects of a common pro-inflammatory stimulus, IL-1beta, on the hippocampus, substantia nigra, striatum and cortex. We determined various responses, including cytokine mRNA induction, glial activation, immune cell infiltration and changes in neuronal integrity, in both injected and adjacent regions 1 and 6 days after the injection of IL-1beta. We found that the mRNA for TGF-beta was up-regulated in a region-specific manner after IL-1beta administration. Contrary to its response in the periphery, IL-1alpha showed no detectable induction in the tested parenchymal regions. In addition, cytokine induction was also sometimes observed in regions distant from the site of injection. Interestingly, IL-1beta-mediated neurodegeneration was observed in the dentate gyrus of the hippocampus, but not in the other tested regions. The cellular recruitment mediated by IL-1 beta injection consisted mainly of polymorphonuclear cells (PMN), which correlated with IL-1betamRNA induction even in regions far from the injection site. These results indicate that various parenchymal regions show different inflammatory responses and neurodegeneration in response to IL-1beta. Taken together, our results provide a more precise picture of regional inflammation in the brain and should provide a basis for differential interpretation of results based on regional inflammatory differences.