Cytokines are powerful mediators of biologic responses in the CNS and may contribute to cellular injury in pathophysiologic states. In order to better understand the actions of cytokines in the intact mammalian CNS, a transgenic approach was employed that targeted the expression of different cytokines to astrocytes in mice. Fusion gene constructs consisting of a GFAP expression vector into which was inserted the DNA encoding the cytokines interleukin-6 (IL-6), IL-3, or TNF-alpha were used to generate transgenic mice. Expression of the transgene-encoded cytokines in astrocytes was confirmed at both the RNA and protein levels. Transgenic mice were subject to multilevel analysis to determine the extent of structural and functional CNS alterations. Transgenic mice exhibited distinct adult-onset, chronic-progressive neurological disorders that correlated with the level and anatomic distribution of transgene-encoded cytokine expression. The principal findings were neurodegeneration and cognitive decline due to IL-6 expression, macrophage/microglial-mediated primary demyelination with motor disease resulting from IL-3 expression, and lymphocytic meningoencephalomyelitis with paralysis induced by TNF-alpha expression. These transgenic models (1) indicate that expression of cytokines per se in the intact CNS is pathogenic, with cytokine-specific neural cell injury leading to unique functional deficits; (2) recapitulate many of the structural and functional changes seen in human inflammatory neurological disorders; (3) provide a valuable tool for advancing our understanding of the CNS pathobiology of cytokines; and (4) offer a unique resource for the development and testing of therapies aimed at abrogating the harmful actions of these important mediators.