NR ACEI
AU Campbell,I.L.; Eddleston,M.; Kemper,P.; Oldstone,M.B.A.; Hobbs,M.V.
TI Activation of cerebral cytokine gene expression and its correlation with onset of reactive astrocyte and acute-phase response gene expression in scrapie
QU Journal of Virology 1994 Apr; 68(4): 2383-7
PT journal article
AB The pathogenesis of scrapie, a transmissible subacute spongiform encephalopathy, is unclear. However, certain aspects of the known cellular and molecular neuropathology in scrapie led us to hypothesize that cytokines could mediate cerebral pathological changes in this neurodegenerative disease. Therefore, expression of multiple cytokine genes in the brain and peripheral organs of scrapie-infected mice was examined. Late in the course of scrapie, expression of tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and IL-1 beta mRNA was markedly increased in the brain but not the spleen, kidneys, or liver. In time course studies, scrapie-infected mice exhibited increased cerebral expression of the TNF-alpha, IL-1 alpha, and IL-1 beta mRNAs by week 15 postinoculation - a time point that coincided with the onset of clinical symptoms. Thereafter, the levels of these cytokine transcripts increased progressively to the terminal stages of of the disease (week 25). To determine the relationship of the increased cerebral expression of the cytokine mRNAs to the development of pathological changes in scrapie, we examined the expression of the glial fibrillary acidic protein gene (a marker for astrocytosis) and the murine acute-phase response gene homologous to the alpha 1-antichymotrypsin gene (designated EB22/5.3). Markedly increased expression of both the glial fibrillary acidic protein and EB22/5.3 mRNAs was observed in the brain but not the peripheral organs of scrapie-infected mice. The increased expression of both these gene products also occurred at week 15 of infection and, thereafter, increased progressively to the terminal stages of the disease. Therefore, infection of mice with scrapie resulted in significant increases in the expression of the TNF-alpha, IL-1 alpha, and IL-1 beta gene products, whose pattern correlated with the onset and development of molecular and clinical pathological changes. Since scrapie is known not to evoke an immune response, the present findings strongly suggest the existence of a localized cerebral host response to the agent during which proinflammatory cytokines could be key pathogenic mediators.
IN In den Gehirnen, jedoch nicht in Milz, Nieren oder Leber scrapieinfizierter Mäuse beginnt mit dem Einsetzen der ersten Symptome eine bis zum Tod der Tiere fortschreitende Zunahme der Expression der Cytokine Tumornekrosefaktor alpha (TNF-alpha), Interleukin-1 alpha (IL-1 alpha) und IL-1 beta. Dies spricht für eine lokale Reaktion des Gehirns auf Prionkrankheiten, während das Immunsystem bekanntlich nicht reagiert.
MH Acute-Phase Reaction; Animal; Astrocytes/metabolism; Brain/*metabolism; Cytokines/*genetics; *Gene Expression Regulation; Interleukin-1/genetics; Male; Mice; Mice, Inbred Strains; RNA, Messenger/*biosynthesis; Scrapie/*genetics; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Time Factors; Tissue Distribution; Tumor Necrosis Factor/genetics
AD Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037.
SP englisch
PO USA