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Role of the JAKs/STATs pathway in the intracellular calcium changes induced by interleukin-6 in hippocampal neurons

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Abstract

Recent studies show that inflammation has an active role in the onset of neurodegenerative diseases. It is known that in response to extracellular insults microglia and/or astrocytes produce inflammatory agents. These contribute to the neuropathological events in the aging process and neuronal degeneration. Interleukin-6 (IL-6) has been involved in the pathogenesis of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Here, we show that IL-6 treatment of rat hippocampal neurons increases the calcium influx via NMDA-receptor, an effect that is prevented by the specific NMDA receptor antagonist MK-801 (dizocilpine). We also show that this calcium influx is mediated by the JAKs/STATs pathway, since the inhibitor of JAKs/STATs pathway, JAK 3 inhibitor, blocks calcium influx even in the presence of IL-6. This increase in calcium signal was dependent on external sources, since this signal was not observed in the presence of EGTA. Additional studies indicate that the increase in cytosolic calcium induces tau protein hyperphos-phorylation, as revealed by using specific antibodies against Alzheimer phosphoepitopes. This anomalous tau hyperphosphorylation was dependent on both the JAKs/STATs pathway and NMDA receptor. These results suggest that IL-6 would induce a cascade of molecular events that produce a calcium influx through NMDA receptors, mediated by the JAKs/STATs pathway, which subsequently modifies the tau hyperphosphorylation patterns.

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Abbreviations

Aß:

Amyloid beta peptide

AD:

Alzheimer’s disease

IL-6:

interleukin-6

NMDA:

N-methyl-D-aspartate

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Authors and Affiliations

  1. Laboratory of Cellular, Molecular Biology and Neurosciences, Millennium Institute for Advanced Studies in Cell Biology and Biotechnology (CBB), Department of Biology, Faculty of Sciences, Philadelphia

    Daniel I. Orellana, Rodrigo A. Quintanilla, Christian Gonzalez-Billault & Ricardo B. Maccioni

  2. Department of Neurological Sciences, Faculty of Medicine, Universidad de Chile, Las Encinas 3370, Ñuñoa, Santiago, Chile

    Ricardo B. Maccioni

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  1. Daniel I. Orellana
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  2. Rodrigo A. Quintanilla
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  3. Christian Gonzalez-Billault
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  4. Ricardo B. Maccioni
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Correspondence to Ricardo B. Maccioni.

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Orellana, D.I., Quintanilla, R.A., Gonzalez-Billault, C. et al. Role of the JAKs/STATs pathway in the intracellular calcium changes induced by interleukin-6 in hippocampal neurons. neurotox res 8, 295–304 (2005). https://doi.org/10.1007/BF03033983

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  • DOI: https://doi.org/10.1007/BF03033983

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