Amyloid β Peptide Potentiates Cytokine Secretion by Interleukin-1 β-Activated Human Astrocytoma Cells

Neurodegenerative processes in Alzheimer disease (AD) are thought to be driven in part by the deposition of amyloid β (Aβ), a 39- to 43-amino acid peptide product resulting from an alternative cleavage of amyloid precursor protein. Recent descriptions of in vitro neurotoxic effects of Aβ support this hypothesis and suggest toxicity might be mediated by Aβ-induced neuronal calcium disregulation. In addition, it has been reported that "aging" Aβ results in increased toxic potency due to peptide aggregation and formation of a β-sheet secondary structure. In addition, Aβ might also promote neuropathology indirectly by activating immune/inflammatory pathways in affected areas of the brain (e.g., cortex and hippocampus). Here we report that Aβ can modulate cytokine secretion [interleukins 6 and 8 (IL-6 and IL-8)] from human astrocytoma cells (U-373 MG). Freshly prepared and aged Aβ modestly stimulated IL-6 and IL-8 secretion from U-373 MG cells. However, in the presence of interleukin-1β (IL-1β), aged, but not fresh, Aβ markedly potentiated (3- to 8-fold) cytokine release. In contrast, aged Aβ did not potentiate substance P (NK-1)- or histamine (H1)-stimulated cytokine production. Further studies showed that IL-1β-induced cytokine release was potentiated by Aβ-(25-35), while Aβ-(1-16) was inactive. Calcium disregulation may be responsible for the effects of Aβ on cytokine production, since the calcium ionophore A23187 similarly potentiated IL-1β-induced cytokine secretion and EGTA treatment blocked either Aβ or A23187 activity. Thus, chronic neurodegeneration in AD-affected brain regions may be mediated in part by the ability of Aβ to exacerbate inflammatory pathways in a conformation-dependent manner.