title: Interaction of interleukin-1beta with muscarinic acetylcholine receptor-mediated signaling cascade in cholinergically differentiated SH-SY5Y cells.
abstract: 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.
authors.affiliation: Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, Leipzig, Germany. schre@medizin.uni-leipzig.de
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schliebs
authors.forename: Kristin
authors.initials: K
authors.lastname: Heidel
authors.forename: Jenny
authors.initials: J
authors.lastname: Apelt
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gniezdzinska
authors.forename: Ludmil
authors.initials: L
authors.lastname: Kirazov
authors.forename: Andrzej
authors.initials: A
authors.lastname: Szutowicz
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D002217:Carbachol / Q000008:administration & dosage; D018679:Cholinergic Agonists / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006868:Hydrolysis; D053583:Interleukin-1beta / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D018679:Cholinergic Agonists; D053583:Interleukin-1beta; D016328:NF-kappa B; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D018808:Transcription Factor AP-1; D002217:Carbachol; D000110:Acetylcholinesterase