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

J Neurochem. 2006 Sep;98(5):1379-89. doi: 10.1111/j.1471-4159.2006.03951.x. Epub 2006 Jun 12.


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

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Anterior Hypothalamic Nucleus / cytology*
  • Blotting, Western / methods
  • Cells, Cultured
  • Ceramides / pharmacology*
  • Dose-Response Relationship, Drug
  • Embryo, Mammalian
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agents / pharmacology
  • Glial Fibrillary Acidic Protein / metabolism
  • Immunohistochemistry / methods
  • Immunoprecipitation / methods
  • Interleukin-1 / pharmacology*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Membrane Potentials / radiation effects
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / metabolism
  • Myeloid Differentiation Factor 88
  • Neuroglia / drug effects
  • Neurons / drug effects*
  • Neurons / physiology
  • Patch-Clamp Techniques / methods
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Receptors, Interleukin-1 / deficiency
  • Time Factors


  • Adaptor Proteins, Signal Transducing
  • Ceramides
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agents
  • Glial Fibrillary Acidic Protein
  • Interleukin-1
  • Microtubule-Associated Proteins
  • Mtap2 protein, mouse
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Interleukin-1
  • Proto-Oncogene Proteins pp60(c-src)