To investigate whether activation of the liver X receptors (LXRs) inhibits amyloid beta(1-40) (A beta(1-40)) induced inflammatory and senescent responses in human retinal pigment epithelial (RPE) cells. Confluent cultures of human primary RPE and ARPE-19 cells pretreated with 5 mu Ie of TO901317 (TO90), a synthetic agonist of LXR, or vehicle were incubated with 1 mu Ie of A beta(1-40) or A beta(40-1). The optimum concentrations of A beta(1-40) and TO90 were determined by cell viability assay. Pro-inflammatory cytokines IL-6, IL-8, MCP-1 were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Expression and localization of an aging protein p16INK4a (p16) were analyzed by western blotting and immunofluorescence. Expressions of LXRs and one of their target genes ATP-binding cassette transporter A1 (ABCA1) were examined by real-time PCR and western blotting. Phosphorylated transcription inhibition factor-kappa B-alpha (p-I kappa B-alpha) was assessed by western blotting. A negative linear relationship between the A beta(1-40) concentration and the cell viability was evident, indicating A beta(1-40) decreased ARPE-19 cell viability in a dose-dependent manner. A beta(1-40) enhanced the expression of IL-6, IL-8, MCP-1 as well as p16 in both RPE cell lines at both mRNA and protein levels, whereas TO90 counteracted the detrimental effects. TO90 upregulated the expression of LXR alpha and its target gene ABCA1, but it did not affect the expression of LXR beta. Meanwhile, TO90 inhibited the phosphorylation of I kappa B-alpha mediated by A beta(1-40) stimulation. Activation of the LXR alpha-ABCA1 axis may alleviate A beta(1-40) induced inflammatory and senescent responses in RPE cells. The beneficial effect appears associated with the inhibition of the NF-kappa B signaling pathway.