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

Brain Research

Tumor Cells, Cultured, Acetylcholinesterase, metabolism, Transcription Factor AP-1, physiology, drug effects, Signal Transduction, Second Messenger Systems, Receptors, Muscarinic, Phosphatidylinositols, cytology, Neurons, Neuroblastoma, NF-kappa B, Interleukin-1beta, Hydrolysis, Humans, Dose-Response Relationship, Drug, administration & dosage, Cholinergic Agonists, Carbachol, Alzheimer Disease

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      Increased expression of interleukin (IL)-1beta has been found in Alzheimer brain, raising the question whether plaque-associated up-regulation of IL-1beta may contribute to neurodegeneration. IL-1beta 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-1beta in specific cholinergic cell loss. To reveal whether IL-1beta affects muscarinic acetylcholine receptor (mAChR)-mediated intracellular signaling, cholinergically differentiated SH-SY5Y cells were exposed to IL-1beta 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 NFkappaB and AP-1, and activity of acetylcholinesterase (AChE). Carbachol stimulation of SH-SY5Y cells dose-dependently stimulated the activation of the transcription factors NFkappaB 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-1beta completely suppressed the carbachol response. mAChR-mediated enhancements of AChE activity by carbachol were impaired following pre-exposure of SH-SY5Y cells with IL-1beta, already detectable at a concentration of 1 ng/ml and 1 h of exposure time. The data indicate that IL-1beta may interfere with the cholinergic signal transduction cascade by inhibiting transcription factor activation, thus providing another mechanism by which IL-1beta may induce cholinergic dysfunction in Alzheimer's disease.

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