title: Human amylin stimulates inflammatory cytokine secretion from human glioma cells.
abstract: Chronic neurodegeneration in the brains of Alzheimer's disease (AD) patients may be mediated, at least in part, by the ability of amyloid beta (Abeta) to exacerbate inflammatory pathways in a conformation-dependent manner. In this regard, we previously reported that the Abeta-peptide-mediated potentiation of inflammatory cytokine secretion from interleukin-1beta (IL-1beta)-stimulated human astrocytoma cells was conformation dependent. Other amyloidogenic peptides, such as human amylin, which display similar conformation-dependent neurotoxic effects, may also elicit inflammatory cytokine secretion from glial cells. To test this hypothesis, we compared human and rat amylin for the effects on cytokine production in U-373 MG human astrocytoma cells. Human amylin alone stimulated U-373 MG cells to secrete IL-6 and IL-8 in a concentration-dependent manner with maximum effects seen at 10-25 microM peptide. In addition, human amylin markedly potentiated IL-1beta-stimulated cytokine production with a similar concentration dependence. In contrast, nonamyloidogenic rat amylin modestly stimulated cytokine secretion, either alone or combined with IL-1beta. Aging human amylin resulted in diminished cytokine secretion, probably due to the formation of large, less active aggregates. In agreement with our previous studies using Abeta, extracellular Ca(2+) was necessary for human amylin stimulation of cytokine secretion. Our data suggest that amyloidogenic peptides promote cytokine secretion through similar beta-sheeted secondary-structure- and extracellular-Ca(2+)-dependent mechanisms.
authors.affiliation: Neuroscience Diseases Research Division, Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285, USA. gitter_bruce_d@Lilly.com
authors.forename: B D
authors.initials: BD
authors.lastname: Gitter
authors.forename: L M
authors.initials: LM
authors.lastname: Cox
authors.forename: C D
authors.initials: CD
authors.lastname: Carlson
authors.forename: P C
authors.initials: PC
authors.lastname: May
mesh_terms: D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D001254:Astrocytoma / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004533:Egtazic Acid / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D058228:Islet Amyloid Polypeptide; D009363:Neoplasm Proteins / Q000378:metabolism*; D009410:Nerve Degeneration; D017433:Protein Structure, Secondary; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D016207:Cytokines; D007375:Interleukin-1; D058228:Islet Amyloid Polypeptide; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D004533:Egtazic Acid; D002118:Calcium