Neuron-Specific Effects of Interleukin-1β Are Mediated by a Novel Isoform of the IL-1 Receptor Accessory Protein

In the CNS, interleukin-1 beta (IL-1 beta) is synthesized and released during injury, infection, and disease, mediating inflammatory responses. However, IL-1 beta 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-1 beta induced both the p38 MAPK and NF-kappa B (nuclear factor kappa B) pathways regulating inflammatory responses, however in hippocampal neurons IL-1 beta activated p38 but not NF-kappa B. Additionally, IL-1 beta 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-1 beta 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-1 beta regulation of p-Src in neurons. AcPb also played a modulatory role in the activation of p38 MAPK, but had no effect on NF-kappa B signaling. The restricted expression of AcPb in CNS neurons, therefore, governs specific neuronal signaling and functional responses to IL-1 beta.