IL-1beta induces a MyD88-dependent and ceramide-mediated activation of Src in anterior hypothalamic neurons.
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.
Davis
Christopher N
CN
The Harold L. Dorris Neurological Research Institute and Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California 92037, USA.
Tabarean
Iustin
I
Gaidarova
Svetlana
S
Behrens
M Margarita
MM
Bartfai
Tamas
T
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D007025:Anterior Hypothalamic Nucleus / Q000166:cytology*; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D007375:Interleukin-1 / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000172:deficiency; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D002518:Ceramides; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D005904:Glial Fibrillary Acidic Protein; D007375:Interleukin-1; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D016392:Proto-Oncogene Proteins pp60(c-src)