Cytokines have roles in tumor biology and induce neurological manifestations. Cytokines produced in response to a brain tumor may generate neurological manifestations via paracrine action. We investigated cytokine modulation in an in vivo brain tumor model with behavioral, morphological, and molecular approaches. Rat C6 glioma cells were implanted into the third cerebral ventricle of Wistar rats, their behavior was monitored, and the development of an intracranial tumor of astrocytic origin was confirmed by histology and positive immunostaining for vimentin, S-100 protein, and glial fibrillary acidic protein. Sensitive and specific RNase protection assays were used to analyze cytokine messenger RNA (mRNA) in brain regions from anorexic brain tumor-bearing animals. Brain tumor formation was associated with significant increased levels of interleukin (IL)-1β, IL-1 receptor antagonist, IL-1 receptor type I, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 mRNAs in the cerebellum, hippocampus, and hypothalamus. IL-1 receptor accessory proteins I and II mRNAs were increased in the cerebellum and hypothalamus. We also examined hypothalamic feeding-associated components: neuropeptide Y and proopiomelanocortin mRNAs were down-regulated, glycoprotein 130 mRNA levels were up-regulated, and leptin receptor (OB-R) mRNA levels were unchanged. These dissimilar profiles of mRNA expression suggest specificity of brain tumor-induced transcriptional changes. The data implicate cytokines as important factors in brain tumor- host interactions in vivo. The data also show that the C6 cell-induced glioma can be used as a behavioral-molecular model to study cytokine and neuropeptide modulation and action during the host biochemical and physiological responses to brain tumor development. Paracrine interactions seem pivotal because cytokine modulation was observed in various brain regions. These results also suggest that cytokine and neuropeptide changes during brain tumor progression are involved in brain tumor-associated neurological and neuropsychiatrical manifestations.
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