Immunological mechanisms, including stimulation of brain microglia and elevation of various inflammatory cytokines, have been implicated in the pathogenesis of Alzheimer's disease, where accumulation of β-amyloid peptide (Aβ) is one of its main pathological features. In this study we investigated the interaction of human monocyte-like cells with synthetic β-amyloid peptide Aβ(1–40) and its subfragment Aβ(25–35). THP-1 cells (a transformed human monocyte cell line) were used with or without prior differentiation by phorbol myristate acetate (PMA), and cell activation was assessed by the secretion of tumor necrosis factor-α (TNF-α). First, it was shown that THP-1 cells could be induced to secrete significant amounts of TNF-α by interleukin-1, lipopolysaccharide, interferon-γ (IFN-γ) and PMA alone or in combination with each other. Next it was shown that Aβ(1–40) could also induce secretion of TNF-α by THP-1 cells, but the effect was diminished when this peptide was applied in combination with IFN-γ. The Aβ subfragment Aβ(25–35) was ineffective in inducing TNF-α production. The cellular action of Aβ(1–40) appears to involve protein kinase C since pretreatment of THP-1 cells by PMA or the protein kinase C inhibitor H-7 diminished the cellular response to Aβ(1–40). Identification of the pathway by which extracellular Aβ activates the intracellular PKC-dependent secretion of TNF-α may help in developing new therapeutic strategies for Alzheimer's disease.