Heightened expression of tumor necrosis factor alpha, interleukin 1 alpha, and glial fibrillary acidic protein in experimental Creutzfeldt-Jakob disease in mice.
The ultrastructural pathology of myelinated axons in mice infected experimentally with the Fujisaki strain of Creutzfeldt-Jakob disease (CJD) virus is characterized by myelin sheath vacuolation that closely resembles that induced in murine spinal cord organotypic cultures by tumor necrosis factor alpha (TNF-alpha), a cytokine produced by astrocytes and macrophages. To clarify the role of TNF-alpha in experimental CJD, we investigated the expression of TNF-alpha in brain tissues from CJD virus-infected mice at weekly intervals after inoculation by reverse transcription-coupled PCR, Northern and Western blot analyses, and immunocytochemical staining. Neuropathological findings by electron microscopy, as well as expression of interleukin 1 alpha and glial fibrillary acidic protein, were concurrently monitored. As determined by reverse transcription-coupled PCR, the expression of TNF-alpha, interleukin 1 alpha, and glial fibrillary acidic protein was increased by approximately 200-fold in the brains of CJD virus-inoculated mice during the course of disease. By contrast, beta-actin expression remained unchanged. Progressively increased expression of TNF-alpha in CJD virus-infected brain tissues was verified by Northern and Western blot analyses, and astrocytes in areas with striking myelin sheath vacuolation were intensely stained with an antibody against murine TNF-alpha. The collective findings of TNF-alpha overexpression during the course of clinical disease suggest that TNF-alpha may mediate the myelin sheath vacuolation observed in experimental CJD.
Kordek
R
R
Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke. National Institutes of Health, Bethesda, MD 20892, USA.
Nerurkar
V R
VR
Liberski
P P
PP
Isaacson
S
S
Yanagihara
R
R
Gajdusek
D C
DC
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009186:Myelin Sheath / Q000648:ultrastructure; D016133:Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation
D005904:Glial Fibrillary Acidic Protein; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha