title: Neuron-specific effects of interleukin-1β are mediated by a novel isoform of the IL-1 receptor accessory protein.
abstract: In the CNS, interleukin-1β (IL-1β) is synthesized and released during injury, infection, and disease, mediating inflammatory responses. However, IL-1β is also present in the brain under physiological conditions, and can influence hippocampal neuronal function. Several cell-specific IL-1-mediated signaling pathways and functions have been identified in neurons and astrocytes, but their mechanisms have not been fully defined. In astrocytes, IL-1β induced both the p38 MAPK and NF-κB (nuclear factor κB) pathways regulating inflammatory responses, however in hippocampal neurons IL-1β activated p38 but not NF-κB. Additionally, IL-1β induced Src phosphorylation at 0.01 ng/ml in hippocampal neurons, a dose 1000-fold lower than that used to stimulate inflammatory responses. IL-1 signaling requires the type 1 IL-1 receptor and the IL-1 receptor accessory protein (IL-1RAcP) as a receptor partner. We previously reported a novel isoform of the IL-1RAcP, IL-1RAcPb, found exclusively in CNS neurons. In this study, we demonstrate that AcPb specifically mediates IL-1β activation of p-Src and potentiation of NMDA-induced calcium influx in mouse hippocampal neurons in a dose-dependent manner. Mice lacking the AcPb, but retaining the AcP, isoform were deficient in IL-1β regulation of p-Src in neurons. AcPb also played a modulatory role in the activation of p38 MAPK, but had no effect on NF-κB signaling. The restricted expression of AcPb in CNS neurons, therefore, governs specific neuronal signaling and functional responses to IL-1β.
authors.affiliation: Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, USA.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Huang
authors.forename: Dirk E
authors.initials: DE
authors.lastname: Smith
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Ibáñez-Sandoval
authors.forename: John E
authors.initials: JE
authors.lastname: Sims
authors.forename: Wilma J
authors.initials: WJ
authors.lastname: Friedman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation; D053577:Interleukin-1 Receptor Accessory Protein / Q000172:deficiency / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D020033:Protein Isoforms / Q000172:deficiency / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053577:Interleukin-1 Receptor Accessory Protein; D053583:Interleukin-1beta; D016328:NF-kappa B; C121001:NR2B NMDA receptor; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium