Abstract
It was previously observed that IL-1beta interferes with BDNF-induced TrkB-mediated signal transduction and protection of cortical neurons from apoptosis evoked by deprivation from trophic support [Tong L., Balazs R., Soiampornkul R., Thangnipon W., Cotman C.W., 2007. Interleukin-1beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol. Aging]. Here we investigated whether the effect of the cytokine on neurotrophin signaling is more general. The influence of IL-1beta on NT-3 signaling was therefore studied under conditions when NT-3 primarily activated the TrkC receptor. The cytokine reduced NT-3-induced activation of MAPK/ERK and Akt, but did not interfere with Trk receptor autophosphorylation. IL-1beta reduced tyrosine phosphorylation of the docking proteins, IRS-1 and Shc, which convey receptor activation to the downstream protein kinase cascades. These are the steps that are also inhibited by IL-1beta in BDNF-induced signal transduction. The functional consequences of the effect of IL-1beta on NT-3 signaling were severe, as NT-3 protection of the trophic support-deprived cortical neurons was abrogated. In view of the role in the maintenance and plasticity of neurons of ERK, Akt and CREB, which are activated by neurotrophins, elevated IL-1beta levels in the brain in Alzheimer's disease and other neurodegenerative diseases might contribute to the decline in cognitive functions before the pathological signs of the disease develop.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Adaptor Proteins, Signal Transducing / drug effects
-
Adaptor Proteins, Signal Transducing / metabolism
-
Animals
-
Cells, Cultured
-
Cerebral Cortex / immunology*
-
Cerebral Cortex / metabolism
-
Cerebral Cortex / physiopathology
-
Cyclic AMP Response Element-Binding Protein / metabolism
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
Insulin Receptor Substrate Proteins
-
Interleukin-1beta / immunology*
-
Interleukin-1beta / metabolism
-
Interleukin-1beta / pharmacology
-
MAP Kinase Signaling System / drug effects
-
MAP Kinase Signaling System / physiology
-
Nerve Degeneration / immunology*
-
Nerve Degeneration / metabolism
-
Nerve Degeneration / physiopathology
-
Neurodegenerative Diseases / immunology
-
Neurodegenerative Diseases / metabolism
-
Neurodegenerative Diseases / physiopathology
-
Neurons / drug effects
-
Neurons / immunology*
-
Neurons / metabolism
-
Neurotrophin 3 / drug effects
-
Neurotrophin 3 / metabolism*
-
Oncogene Protein v-akt / metabolism
-
Rats
-
Receptor, trkC / agonists
-
Receptor, trkC / metabolism
-
Shc Signaling Adaptor Proteins
-
Signal Transduction / drug effects
-
Signal Transduction / immunology
-
Src Homology 2 Domain-Containing, Transforming Protein 1
Substances
-
Adaptor Proteins, Signal Transducing
-
Cyclic AMP Response Element-Binding Protein
-
Insulin Receptor Substrate Proteins
-
Interleukin-1beta
-
Irs1 protein, rat
-
Neurotrophin 3
-
Shc Signaling Adaptor Proteins
-
Shc1 protein, rat
-
Src Homology 2 Domain-Containing, Transforming Protein 1
-
Receptor, trkC
-
Oncogene Protein v-akt
-
Extracellular Signal-Regulated MAP Kinases