Interleukin-6 protects rat PC12 cells from serum deprivation or chemotherapeutic agents through the phosphatidylinositol 3-kinase and STAT3 pathways

Neurosci Lett. 2001 Aug 17;309(1):13-6. doi: 10.1016/s0304-3940(01)02012-2.

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

  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cell Survival / drug effects*
  • Cell Survival / physiology
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism
  • Culture Media, Serum-Free / pharmacology
  • DNA-Binding Proteins / drug effects*
  • DNA-Binding Proteins / metabolism
  • Drug Interactions / physiology
  • Enzyme Inhibitors / pharmacology
  • Growth Inhibitors / pharmacology
  • Interleukin-6 / metabolism
  • Interleukin-6 / pharmacology*
  • Leukemia Inhibitory Factor
  • Lymphokines / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • PC12 Cells / drug effects*
  • PC12 Cells / metabolism
  • Phosphatidylinositol 3-Kinases / drug effects*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • STAT3 Transcription Factor
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Trans-Activators / drug effects*
  • Trans-Activators / metabolism
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology

Substances

  • Antineoplastic Agents
  • Culture Media, Serum-Free
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Growth Inhibitors
  • Interleukin-6
  • Leukemia Inhibitory Factor
  • Lymphokines
  • Neuroprotective Agents
  • Proto-Oncogene Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Trans-Activators
  • Phosphatidylinositol 3-Kinases
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt