Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 275, Issue 11, Pages 7918-7924Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.275.11.7918
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Funding
- NIA NIH HHS [AG13939, AG15501] Funding Source: Medline
- NIGMS NIH HHS [GM08061] Funding Source: Medline
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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.
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