TUMOR-NECROSIS-FACTOR-ALPHA EXPRESSION IN THE BRAIN DURING FATAL MURINE CEREBRAL MALARIA - EVIDENCE FOR PRODUCTION BY MICROGLIA AND ASTROCYTES

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.