TNF-ALPHA EXPRESSION BY RESIDENT MICROGLIA AND INFILTRATING LEUKOCYTES IN THE CENTRAL-NERVOUS-SYSTEM OF MICE WITH EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS - REGULATION BY TH1 CYTOKINES

The inflammatory cytokines IFN-gamma and TNF-alpha have been demonstra ted in various autoimmune diseases, and are thought to participate in the induction and pathogenesis of disease. TFN-alpha is a cytopathic c ytokine that is cytotoxic for oligodendrocytes in vitro and has been i mplicated in the pathology of multiple sclerosis and its animal model experimental allergic encephalomyelitis (EAE). We used reverse transcr iptase (RT)-PCR to study the kinetics, cellular source, and regulation of cytokine gene expression in the central nervous system (CNS) of SJ L/J mice with myelin basic protein-induced EAE at different stages of the disease. The expression of CD3, IL-2, IFN-gamma, and TNF-alpha mRN A was barely detectable in the CNS of unmanipulated mice or mice that were immunized with adjuvant but showed no symptoms. These mRNAs were readily detectable in the CNS of mice during peak disease, then coordi nately dropped to background levels during remission. Analysis of cell s isolated from the CNS of mice with acute EAE showed that the Th1 cyt okines, IL-2 and IFN-gamma, were produced by infiltrating CD4(+) T cel ls. In contrast, TNF-alpha was predominantly transcribed by non-T mono nuclear CNS cells, the majority of which were identified as microglia and macrophages by their Mac-1 phenotype. Microglia could be discrimin ated by their low expression of CD45. Incubation of freshly derived, a dult microglia from normal, uninfiltrated, CNS with activated Th1 supe rnatant induced the production of TNF-alpha mRNA. Therefore, TNF-alpha is made by both CNS-resident microglia and infiltrating macrophages d uring EAE, and this production is tightly controlled by cytokines secr eted by infiltrating CD4(+) T cells.