Interaction of interleukin-1β with muscarinic acetylcholine receptor-mediated signaling cascade in cholinergically differentiated SH-SY5Y cells

Increased expression of interleukin (IL)-1β has been found in Alzheimer brain, raising the question whether plaque-associated up-regulation of IL-1β may contribute to neurodegeneration. IL-1β is capable to induce a number of events that also occur in Alzheimer's disease such as stimulation of the amyloidogenic pathway of amyloid precursor protein processing. However, less is known on participation of IL-1β in specific cholinergic cell loss. To reveal whether IL-1β affects muscarinic acetylcholine receptor (mAChR)-mediated intracellular signaling, cholinergically differentiated SH-SY5Y cells were exposed to IL-1β for various periods of time followed by stimulation of mAChR with carbachol for 1 h, and key molecules of cholinergic signaling cascades were determined including phosphoinositide hydrolysis, DNA-binding capacity of NFκB and AP-1, and activity of acetylcholinesterase (AChE).Carbachol stimulation of SH-SY5Y cells dose-dependently stimulated the activation of the transcription factors NFκB and AP-1 as revealed by electrophoretic mobility shift assay (EMSA), while pre-exposure of SH-SY5Y cells for 24 h with 1 ng/ml IL-1β completely suppressed the carbachol response. mAChR-mediated enhancements of AChE activity by carbachol were impaired following pre-exposure of SH-SY5Y cells with IL-1β, already detectable at a concentration of 1 ng/ml and 1 h of exposure time. The data indicate that IL-1β may interfere with the cholinergic signal transduction cascade by inhibiting transcription factor activation, thus providing another mechanism by which IL-1β may induce cholinergic dysfunction in Alzheimer's disease.