Im. Medana et al., TUMOR-NECROSIS-FACTOR-ALPHA EXPRESSION IN THE BRAIN DURING FATAL MURINE CEREBRAL MALARIA - EVIDENCE FOR PRODUCTION BY MICROGLIA AND ASTROCYTES, The American journal of pathology, 150(4), 1997, pp. 1473-1486
Fatal murine cerebral malaria (FMCM) is an immunopathological process.
The depletion of CD4(+) T cells, or the administrations of antioxidan
ts or antibodies against certain cytokines, protect the mice against c
erebral complications. We previously have shown that astrocytes, micro
glia, and monocytes play a role in the development of FMCM, suggesting
that an active immune response occurs locally within the central nerv
ous system. We now have investigated the functional involvement of gli
a and monocytes In FMCM by assessing 1) the production, 2) the tempora
l appearance, and 3) the cellular source of cytokine mRNA and protein
in the brain. Brain sections from uninfected and FMCM mice were analyz
ed for the presence of cytokine mRNA and protein by in situ hybridizat
ion and immunohistochemistry. Tumor necrosis factor (TNF)-alpha mRNA a
nd protein were associated with microglia and astrocytes, monocytes, a
nd the cerebral vascular endothelium in FMCM mice but not uninfected a
nimals. TNF-alpha mRNA was first detected several days before the anim
als showed cerebral symptoms and died. Interleukin (IL)-1 beta mRNA wa
s found ill the brains of both uninfected and FMCM mice. However, IL-1
beta protein was associated only with monocytes, the meningeal vascul
ar endothelium, and neurons in the fronto-parietal cortex in the FMCM
brains. No IL-4 or IL-6 mRNAs were defected in either group. These res
ults provide the strongest evidence to date that cytokines, in particu
lar TNF-alpha, produced locally in the central nervous system play a r
ole in the pathogenesis of FMCM.