Expression of cytokine genes and increased nuclear factor-kappa B activityin the brains of scrapie-infected mice

A number of aspects of the pathogenesis of scrapie remain to be elucidated. The cellular and molecular aspects of the neuropathology in scrapie sugges t the possibility that the proinflammatory cytokines could act as pathogeni c mediators in this neurodegenerative disease, To understand this possibili ty, we examined the expression of proinflammatory cytokine genes in brains of IM mice-infected with 87V scrapie agent. Additionally, we also analyzed the activity of nuclear factor-kappa B (NF-kappa B), which is the major tra nscriptional activator for inflammatory cytokines, and formation of reactiv e oxygen species (ROS) as a common upstream messenger for its activation. T he induction of mRNAs of the inflammatory cytokines, IL-1 alpha, IL-1 beta and TNF-alpha, was detected only in the brains of scrapie-infected mice. Th e activity of NF-kappa B was significantly increased in the nuclear extract s from brains of the scrapie-infected group and the immunoreactivity of NF- kappa B was increased in the hippocampus and thalamus in the brains of scra pie-infected mice. The NF-kappa B immunoreactivity was observed mainly in G FAP-positive astrocytes and also detected in the PrP-amyloid plaques in the brains of 87V scrapie-infected mice. Gene expression of IL-6 and iNOS, the representative target genes for NF-kappa B activation, were activated only in the infected group. The production of ROS was significantly increased i n the brain mitochondrial fractions of scrapie-infected mice. These results suggest that prion accumulation in astrocytes might activate NF-kappa B th rough the increase of ROS generation, and thus alterations in NF-kappa B-di rected gene expression may contribute to both the neurodegeneration and pro inflammatory responses which occur in scrapie. (C) 1999 Elsevier Science B. V. All rights reserved.