Abstract
The mechanisms underlying the anti-apoptotic action of interleukin (IL)-6 on hematopoietic cells have been extensively studied, but those in the case of neuronal cells have been poorly reported. We investigated the effect of IL-6 on the survival of rat PC12 pheochromocytoma cells and analyzed the signaling pathways of the cytokine by means of some kinase inhibitors. IL-6 protects PC12 cells from the death induced by serum deprivation or anticancer agents, such as cisplatin, paclitaxel and 5-fluorouracil. Phosphatidylinositol (PI)3-kinase inhibitors (LY294002 and wortmannin) but not a mitogen-activated protein kinase kinase inhibitor (PD98059) completely suppressed the IL-6-promoted survival of the cells. A Janus tyrosine kinase 2 inhibitor (tyrphostin AG490) suppressed the phosphorylation of signal transducers and activators of transcription (STAT)3 and only partially inhibited the anti-apoptotic activity of IL-6. IL-6 stimulated phosphorylation of Akt, a downstream effector of PI3 kinase, and in the presence of LY294002, the phosphorylation of Akt was reduced to basal level. These results suggest that the signaling pathway for the anti-apoptotic effect of IL-6 in PC12 cells is mediated in major part by activation of the PI3-kinase/Akt pathway and thus is different from that in hematopoietic cells.
MeSH terms
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Animals
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects*
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Apoptosis / physiology
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Cell Survival / drug effects*
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Cell Survival / physiology
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Central Nervous System / drug effects
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Central Nervous System / metabolism
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Culture Media, Serum-Free / pharmacology
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DNA-Binding Proteins / drug effects*
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DNA-Binding Proteins / metabolism
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Drug Interactions / physiology
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Enzyme Inhibitors / pharmacology
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Growth Inhibitors / pharmacology
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Interleukin-6 / metabolism
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Interleukin-6 / pharmacology*
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Leukemia Inhibitory Factor
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Lymphokines / pharmacology
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Neurons / drug effects
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Neurons / metabolism
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Neuroprotective Agents / pharmacology*
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PC12 Cells / drug effects*
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PC12 Cells / metabolism
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Phosphatidylinositol 3-Kinases / drug effects*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Rats
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STAT3 Transcription Factor
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Trans-Activators / drug effects*
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Trans-Activators / metabolism
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Transcription, Genetic / drug effects
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Transcription, Genetic / physiology
Substances
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Antineoplastic Agents
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Culture Media, Serum-Free
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DNA-Binding Proteins
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Enzyme Inhibitors
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Growth Inhibitors
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Interleukin-6
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Leukemia Inhibitory Factor
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Lymphokines
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Neuroprotective Agents
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Proto-Oncogene Proteins
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STAT3 Transcription Factor
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Stat3 protein, rat
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Trans-Activators
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt