Human amylin stimulates inflammatory cytokine secretion from human glioma cells

Chronic neurodegeneration in the brains of Alzheimer's disease (AD) patient s may be mediated, at least in part, by the ability of amyloid beta (A beta ) to exacerbate inflammatory pathways in a conformation-dependent manner. I n this regard, we previously reported that the A beta-peptide-mediated pote ntiation of inflammatory cytokine secretion from interleukin-1 beta (IL-1 b eta)-stimulated human astrocytoma cells was conformation dependent. Other a myloidogenic peptides, such as human amylin, which display similar conforma tion-dependent neurotoxic effects, may also elicit inflammatory cytokine se cretion from glial cells. To test this hypothesis, we compared human and ra t amylin for the effects on cytokine production in U-373 MG human astrocyto ma 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 mu M peptide. In addition, human amylin markedly potentiated IL-1 beta-sti mulated cytokine production with a similar concentration dependence. In con trast, nonamyloidogenic rat amylin modestly stimulated cytokine secretion, either alone or combined with IL-1 beta. Aging human amylin resulted in dim inished cytokine secretion, probably due to the formation of large, less ac tive aggregates. In agreement with our previous studies using A beta, extra cellular Ca2+ was necessary for human amylin stimulation of cytokine secret ion. Our data suggest that amyloidogenic peptides promote cytokine secretio n through similar beta-sheeted secondary-structure- and extracellular-Ca2+- dependent mechanism s. Copyright (C) 2000 S. Karger AG, Basel.