Interleukin-6 protects rat PC12 cells from serum deprivation or chemotherapeutic agents through the phosphatidylinositol 3-kinase and STAT3 pathways.
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.
Kunioku
H
H
Saitama Cancer Center Research Institute, 818 Komuro, Ina, 362-0806, Saitama, Japan.
Inoue
K
K
Tomida
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; C494088:Stat3 protein, rat; C494920:Akt1 protein, rat