There is evidence that the cytokine tumor necrosis factor α (TNF-α) contributes to the pathogenesis of neurological autoimmune diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). TNF-α exerts damaging effects on oligodendrocytes, the myelin-producing cell of the central nervous system (CNS), and myelin itself. We have recently demonstrated TNF-α expression from astrocytes induced by lipopolysaccharide (LPS), interferon γ (IFN-γ), and interleukin 1β (IL-1β). Astrocytes secrete TNF-α in response to LPS alone, and can be primed by IFN-γ to enhance LPS-induced TNF-α production. IFN-γ and IL-1β, cytokines known to be present in the CNS during neurological disease states, do not induce TNF-α production alone, but act synergistically to stimulate astrocyte TNF-α expression. Inbred Lewis and Brown-Norway (BN) rats differ in genetic susceptibility to EAE, which is controlled in part by major histocompatibility complex (MHC) genes. We examined TNF-α gene expression by astrocytes derived from BN rats (resistant to EAE) and Lewis rats (highly susceptible). Astrocytes from BN rats express TNF-α mRNA and protein in response to LPS alone, yet IFN-γ does not significantly enhance LPS-induced TNF-α expression, nor do they express appreciable TNF-α in response to the combined stimuli of IFN-γ/IL-1β. In contrast, astrocytes from Lewis rats express low levels of TNF-α mRNA and protein in response to LPS, and are extremely responsive to the priming effect of IFN-γ for subsequent TNF-α gene expression. Also, Lewis astrocytes produce TNF-α in response to IFN-γ/IL-1β. The differential TNF-α production by astrocytes from BN and Lewis strains is not due to the suppressive effect of prostaglandins, because the addition of indomethacin does not alter the differential pattern of TNF-α expression. Furthermore, Lewis and BN astrocytes produce another cytokine, IL-6, in response to LPS, IFN-γ, and IL-1β in a comparable fashion. Peritoneal macrophages and neonatal microglia from Lewis and BN rats are responsive to both LPS and IFN-γ priming signals for subsequent TNF-α production, suggesting that differential TNF-α expression by the astrocyte is cell type specific. Taken together, these results suggest that differential TNF-α gene expression in response to LPS and IFN-γ is strain and cell specific, and reflects both transcriptional and post-transcriptional control mechanisms. The capacity for TNF-α production by Lewis astrocytes, especially in response to disease-related cytokines such as IFN-γ and IL-1β, may contribute to disease susceptibility and to the inflammation and demyelination associated with EAE.