β-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1β- and tumor necrosis factor-α (TNFα)-dependent, and involves a TNFα receptor-associated factor- and NFκB-inducing kinase-dependent signaling mechanism

In Alzheimer's disease, beta-amyloid (AP) plaques are surrounded by activated astrocytes and microglia, A growing body of evidence suggests that these activated glia contribute to neurotoxicity through the induction of inflammatory cytokines such as interleukin (IL)-1 beta and tumor necrosis factor-ac (TNF alpha) and the production of neurotoxic free radicals, mediated in part by the expression of inducible nitric-oxide synthase (iNOS). Here, we address the possibility that A beta-stimulated iNOS expression might result from an initial induction of IL-1 beta and TNF alpha. We find that in A beta-stimulated astrocyte cultures, IL-1 beta and TNF alpha production occur before iNOS production, new protein synthesis is required for increased iNOS mRNA levels, and the IL-I receptor antagonist IL-1 beta can inhibit nitrite accumulation. Likewise, dominant-negative mutants of tumor necrosis factor-alpha receptor-associated factor (TRAF) 6, TRAF2, and NF kappa B-inducing kinase (NIK), intracellular proteins involved in IL-I and TNF alpha! receptor signaling cascades, inhibit A beta-stimulated iNOS promoter activity. Our data suggest that A beta stimulation of astrocyte iNOS is mediated in part by IL-1 beta and TNF alpha, and involves a TRAFG-, TRAF2-, and NIK-dependent signaling mechanism.