Fas/Apo-1 is a member of the TNF receptor superfamily that signals apoptotic cell death in susceptible target cells. Fas or Fas ligand (FasL)- deficient mice are relatively resistant to the induction of experimental allergic encephalomyelitis, implying the involvement of Fas/FasL in this disease process. We have examined the regulation and function of Fas expression in glial cells (astrocytes and microglia). Fas is constitutively expressed by primary murine microglia at a low level and significantly up- regulated by TNF-α or IFN-γ stimulation. Primary astrocytes express high constitutive levels of Fas, which are not further affected by cytokine treatment. In microglia, Fas expression is regulated at the level of mRNA expression; TNF-α and IFN-γ induced Fas mRNA by ~20-fold. STAT-1α and NF- κB activation are involved in IFN-γ- or TNF-α-mediated Fas up-regulation in microglia, respectively. The cytokine TGF-β inhibits basal expression of Fas as well as cytokine-mediated Fas expression by microglia. Upon incubation of microglial cells with FasL-expressing cells, ~20% of cells underwent Fas- mediated cell death, which increased to ~60% when cells were pretreated with either TNF-α or IFN-γ. TGF-β treatment inhibited Fas-mediated cell death of TNF-α- or IFN-γ-stimulated microglial cells. In contrast, astrocytes are resistant to Fas-mediated cell death, however, ligation of Fas induces expression of the chemokines macrophage inflammatory protein-1β (MIP-1β), MIP-1α, and MIP-2. These data demonstrate that Fas transmits different signals in the two glial cell populations: a cytotoxic signal in microglia and an inflammatory signal in the astrocyte.