Background The amyloid precursor protein (APP) and amyloid β (Aβ) peptides support the innate immune defense as an immune receptor, an antimicrobial peptide and an opsonine. In APP-deficient mouse models, a reduced secretion of cytokines has been observed. It is unclear whether this can be attributed to the lack of APP or to the missing secretion of Aβ peptides.Methods In primary human monocyte derived macrophages the secretion of Aβ peptides was inhibited by the γ-secretase inhibitor DAPT or by the β-secretase inhibitor GL-189, applied as a tripartite substance. Alternatively, APP was knocked down by transfection with siRNA. TNFα, IL-6 and IL-10 were measured by ELISA and the phagocytotic activity was evaluated by flow cytometry.Results Reduced concentrations of TNFα and IL-6 were observed in the media of APPk/d macrophages and after inhibition of the β-, or γ-secretase, especially after additional immunological activation with LPS. Secretion of IL-10 was increased after pharmacological inhibition of APP processing when the macrophages were not immunologically activated but was decreased during LPS-induced inflammation in APPk/d macrophages. No changes of the phagocytotic activity were observed.Conclusion We conclude that macrophage APP and Aβ peptides support the initiation of an immune response and are involved in the secretion of TNFα, IL-6 and IL-10.