IL‐1β induces a MyD88‐dependent and ceramide‐mediated activation of Src in anterior hypothalamic neurons

Abstract

The proinflammatory cytokine interleukin1β (IL‐1β), acting at IL‐1R1 receptors, affects neuronal signaling under both physiological and pathophysiological conditions. The molecular mechanism of the rapid synaptic actions of IL‐1β in neurons is not known. We show here that within minutes of IL‐1β exposure, the firing rate of anterior hypothalamic (AH) neurons in culture was inhibited. This effect was prevented by pre‐exposure of the cells to the Src family inhibitor, PP2, suggesting the involvement of Src in the hyperpolarizing effects of IL‐1β. The IL‐1β stimulation of neurons induced a rapid increase in the phosphorylation of the tyrosine kinase Src and kinase suppressor of Ras (ceramide activated protein kinase (CAPK)/KSR) in neurons grown on glia from IL‐1RI(–/–) mice. These effects of IL‐1β were dependent on the association of the cytosolic adaptor protein, MyD88, to the IL‐1 receptor, and on the activation of the neutral sphingomyelinase, leading to production of ceramide. A cell‐permeable analog of ceramide mimicked the effects of IL‐1β on the cultured AH neurons. These results suggest that ceramide may be the second messenger of the fast IL‐1β actions in AH neurons, and that this IL‐1β/ceramide pathway may underlie the fast non‐transcription‐dependent, electrophysiological effects of IL‐1β observed in AH neurons in vivo.