Expression of cytokine genes and increased nuclear factor-kappa B activity in 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 suggest the possibility that the proinflammatory cytokines could act as pathogenic mediators in this neurodegenerative disease. To understand this possibility, 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-kappaB), which is the major transcriptional activator for inflammatory cytokines, and formation of reactive oxygen species (ROS) as a common upstream messenger for its activation. The induction of mRNAs of the inflammatory cytokines, IL-1alpha, IL-1beta and TNF-alpha, was detected only in the brains of scrapie-infected mice. The activity of NF-kappaB was significantly increased in the nuclear extracts from brains of the scrapie-infected group and the immunoreactivity of NF-kappaB was increased in the hippocampus and thalamus in the brains of scrapie-infected mice. The NF-kappaB immunoreactivity was observed mainly in GFAP-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-kappaB activation, were activated only in the infected group. The production of ROS was significantly increased in the brain mitochondrial fractions of scrapie-infected mice. These results suggest that prion accumulation in astrocytes might activate NF-kappaB through the increase of ROS generation, and thus alterations in NF-kappaB-directed gene expression may contribute to both the neurodegeneration and proinflammatory responses which occur in scrapie.
Kim
J I
JI
Institute of Environment and Life Science, Hallym Academy of Sciences and Department of Microbiology, College of Medicine, Hallym University, 1 Ockcheon-Dong, Chuncheon, Kangwon-Do 200-702, South Korea.
Ju
W K
WK
Choi
J H
JH
Choi
E
E
Carp
R I
RI
Wisniewski
H M
HM
Kim
Y S
YS
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000235:genetics; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012608:Scrapie / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse