Beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1beta- and tumor necrosis factor-alpha (TNFalpha)-dependent, and involves a TNFalpha receptor-associated factor- and NFkappaB-inducing kinase-dependent signaling mechanism.
In Alzheimer's disease, beta-amyloid (Abeta) 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)-1beta and tumor necrosis factor-alpha (TNFalpha) 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 Abeta-stimulated iNOS expression might result from an initial induction of IL-1beta and TNFalpha. We find that in Abeta-stimulated astrocyte cultures, IL-1beta and TNFalpha production occur before iNOS production, new protein synthesis is required for increased iNOS mRNA levels, and the IL-1 receptor antagonist IL-1ra can inhibit nitrite accumulation. Likewise, dominant-negative mutants of tumor necrosis factor-alpha receptor-associated factor (TRAF) 6, TRAF2, and NFkappaB-inducing kinase (NIK), intracellular proteins involved in IL-1 and TNFalpha receptor signaling cascades, inhibit Abeta-stimulated iNOS promoter activity. Our data suggest that Abeta stimulation of astrocyte iNOS is mediated in part by IL-1beta and TNFalpha, and involves a TRAF6-, TRAF2-, and NIK-dependent signaling mechanism.
Akama
K T
KT
Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Van Eldik
L J
LJ
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic; D007375:Interleukin-1 / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000097782:NF-kappaB-Inducing Kinase
D016229:Amyloid beta-Peptides; D007375:Interleukin-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; C075222:amyloid beta-protein (1-42); C496318:Nos2 protein, rat