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

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.