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 o n 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 si gnaling pathways of the cytokine by means of some kinase inhibitors. IL-6 p rotects PC12 cells from the death induced by serum deprivation or anticance r agents, such as cisplatin, paclitaxel and 5-fluorouracil. Phosphatidylino sitol (PI)3-kinase inhibitors (LY294002 and wortmannin) but not a mitogen-a ctivated protein kinase kinase inhibitor (PD98059) completely suppressed th e 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 downs tream effector of P13 kinase, and in the presence of LY294002, the phosphor ylation of Akt was reduced to basal level. These results suggest that the s ignaling pathway for the anti-apoptotic effect of IL-6 in PC12 cells is med iated in major part by activation of the P13-kinase/Akt pathway and thus is different from that in hematopoietic cells. (C) 2001 Elsevier Science Irel and Ltd. All rights reserved.