beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1 beta- and tumor necrosis factor-alpha (TNF alpha)-dependent, and involves a TNF alpha receptor-associated factor- and NF kappa B-inducing kinase-dependent signaling mechanism

In Alzheimer's disease, beta-amyloid (AP) plaques are surrounded by activat ed astrocytes and microglia, A growing body of evidence suggests that these activated glia contribute to neurotoxicity through the induction of inflam matory 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 be ta-stimulated astrocyte cultures, IL-1 beta and TNF alpha production occur before iNOS production, new protein synthesis is required for increased iNO S mRNA levels, and the IL-I receptor antagonist IL-1 beta can inhibit nitri te accumulation. Likewise, dominant-negative mutants of tumor necrosis fact or-alpha receptor-associated factor (TRAF) 6, TRAF2, and NF kappa B-inducin g kinase (NIK), intracellular proteins involved in IL-I and TNF alpha! rece ptor signaling cascades, inhibit A beta-stimulated iNOS promoter activity. Our data suggest that A beta stimulation of astrocyte iNOS is mediated in p art by IL-1 beta and TNF alpha, and involves a TRAFG-, TRAF2-, and NIK-depe ndent signaling mechanism.