ACTIVATION OF CEREBRAL CYTOKINE GENE-EXPRESSION AND ITS CORRELATION WITH ONSET OF REACTIVE ASTROCYTE AND ACUTE-PHASE RESPONSE GENE-EXPRESSION IN SCRAPIE

The pathogenesis of scrapie, a transmissible subacute spongiform encep halopathy, is unclear. However, certain aspects of the known cellular and molecular neuropathology in scrapie led us to hypothesize that cyt okines could mediate cerebral pathological changes in this neurodegene rative disease. Therefore, expression of multiple cytokine genes in th e brain and peripheral organs of scrapie-infected mice was examined. L ate in the course of scrapie, expression of tumor necrosis factor alph a (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and IL-1 beta mRNA wa s markedly increased in the brain but not the spleen, kidneys, or live r. In time course studies, scrapie-infected mice exhibited increased c erebral expression of the TNF-alpha, IL-1 alpha, and IL-1 beta mRNAs b y week 15 postinoculation-a time point that coincided with the onset o f clinical symptoms. Thereafter, the levels of these cytokine transcri pts increased progressively to the terminal stages of the disease (wee k 25). To determine the relationship of the increased cerebral express ion of the cytokine mRNAs to the development of pathological changes i n scrapie, we examined the expression of the glial fibrillary acidic p rotein gene (a marker for astrocytosis) and the murine acute-phase res ponse gene homologous to the alpha(1)-antichymotrypsin gene (designate d EB22/5.3). Markedly increased expression of both the glial fibrillar y acidic protein and EB22/5.3 mRNAs was observed in the brain but not the peripheral organs of scrapie-infected mice. The increased expressi on of both these gene products also occurred at week 15 of infection a nd, thereafter, increased progressively to the terminal stages of the disease. Therefore, infection of mice with scrapie resulted in signifi cant increases in the expression of the TNF-alpha, IL-1 alpha, and IL- 1 beta gene products, whose pattern correlated with the onset and deve lopment of molecular and clinical pathological changes. Since scrapie is known not to evoke an immune response, the present findings strongl y suggest the existence of a localized cerebral host response to the a gent during which proinflammatory cytokines could be key pathogenic me diators.