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

Authors

  • Christopher N. Davis,

    1. The Harold L. Dorris Neurological Research Institute and Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California, USA
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  • Iustin Tabarean,

    1. The Harold L. Dorris Neurological Research Institute and Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California, USA
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  • Svetlana Gaidarova,

    1. The Harold L. Dorris Neurological Research Institute and Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California, USA
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  • M. Margarita Behrens,

    1. The Harold L. Dorris Neurological Research Institute and Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California, USA
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  • Tamas Bartfai

    1. The Harold L. Dorris Neurological Research Institute and Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California, USA
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Address correspondence and reprint requests to Tamas Bartfai, The Harold L. Dorris Neurological Research Institute, Molecular and Integrative Neurosciences Department, The Scripps Research Institute, 10550 North Torrey Pines Road, SR-307, La Jolla, CA 92037, USA. E-mail: tbartfai@scripps.edu

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.

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