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

The proinflammatory cytokine interleukin1 beta (IL-1 beta), acting at IL-1R1 receptors, affects neuronal signaling under both physiological and pathophysiological conditions. The molecular mechanism of the rapid synaptic actions of IL-1 beta in neurons is not known. We show here that within minutes of IL-1 beta 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-1 beta. The IL-1 beta 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-1 beta 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-1 beta on the cultured AH neurons. These results suggest that ceramide may be the second messenger of the fast IL-1 beta actions in AH neurons, and that this IL-1 beta/ceramide pathway may underlie the fast non-transcription-dependent, electrophysiological effects of IL-1 beta observed in AH neurons in vivo.