Contribution of Interleukin-1 Receptor Accessory Protein b to Interleukin-1 Actions in Neuronal Cells

Abstract

Interleukin (IL)-1 is an important neuroimmunomodulator and a key mediator of inflammation during brain disorders. It acts on neuronal and glial cells via binding to the IL-1 type 1 receptor and IL-1 receptor accessory protein (IL-1RAcP). More recently, a neuronal-specific isoform of IL-1RAcP, named IL-1RAcPb, has been identified. Our aim was to determine the role of IL-1RAcPb in IL-1 actions in neuronal and glial cells, and to further explore the signaling mechanisms of IL-1 in neurons. We found that IL-1RAcPb deletion had no effect on IL-1α- and IL-1β-induced activation of the extracellular signal-regulated kinase 1/2 or IL-6 release in glial cultures, although IL-6 release in response to high IL-1α concentration (30 IU/ml) was significantly reduced. We identified the p38 kinase as a key signaling element in IL-1α- and IL-1β-induced IL-6 synthesis and release in neuronal cultures. IL-1RAcPb deletion had no effect on IL-1α- and IL-1β-induced IL-6 release in neurons, but significantly reduced IL-1α- but not IL-1β-induced p38 phosphorylation. Our data demonstrate that the p38 signaling pathway plays an important role in IL-1 actions in neurons, and that IL-1RAcP may regulate some, but not all, neuronal activities in response to IL-1α.

The family of the interleukin‐1 receptors

“…Experiments in mice knocked‐out for IL‐1R3b show that this alternative receptor is important for neuroprotection in brain inflammation, whereas it has no involvement in the peripheral effects of IL‐1 . IL‐1R3b KO neurons cannot respond to IL‐1α by inducing phosphorylation of p38 . In agreement with this finding, it was also shown that IL‐1β could induce phosphorylation of p38 and Src, as well as potentiation of NMDA‐induced influx of calcium, in an IL‐1R3b‐dependent manner in neurons .…”

“…The result is a membrane form of IL‐1R3 with an anomalous TIR domain in which the αD helix is disrupted and much longer intracellular tail . IL‐1R3b is exclusively present in the brain, mostly in neurons, but not in microglia or astrocytes . It has been shown that IL‐1R3b can form a complex with IL‐1R1 bound to IL‐1, although there are no univocal data of the downstream signaling initiated by this receptor complex .…”

“…263,264 IL-1R3b is exclusively present in the brain, mostly in neurons, but not in microglia or astrocytes. [264][265][266] It has been shown that IL-1R3b can form a complex with IL-1R1 bound to IL-1, although there are no univocal data of the downstream signaling initiated by this receptor complex. 263,264 Experiments in mice knocked-out for IL-1R3b show that this alternative receptor is important for neuroprotection in brain inflammation, whereas it has no involvement in the peripheral effects of IL-1.…”

Neuronal toll-like receptor 4 signaling induces brain endothelial activation and neutrophil transmigration in vitro

“…Primary neuronal cell cultures were prepared from the brains of mouse embryos at 14 to 16 days of gestation as described previously [17]. Cells were seeded at a density of 6 x 10 5 cells/ml onto poly-D-lysine (PDL)-coated tissue culture plates in neurobasal medium containing 1 U/ml penicillin, 1 μg/ml streptomycin, 1% glutamine, 5% PDS, 2% B27 without antioxidants and 20 μM 5’-fluoro-2-deoxyuridine (FUDR) to inhibit glial cell growth.…”

IL-1RAcPb signaling regulates adaptive mechanisms in neurons that promote their long-term survival following excitotoxic insults

“…Interestingly, AcPb expression is restricted to neurons. Though both proteins modulate MAP kinases activity and in particular the p38 pathway, AcPb, unlike AcP, does not activate canonical NF-κB transcription factors (Huang et al, 2011; Nguyen et al, 2011). Consequently, AcPb signaling has relatively marginal effects of gene transcription compared to AcP.…”