Interleukin-6 activates signal transducer and activator of transcription and mitogen-activated protein kinase signal transduction pathways and induces de novo protein synthesis in human neuronal cells

Interleukin-6 (IL-6) is involved in the pathophysiology of various diseases of the CNS. Because the molecular mechanism of action of this cytokine in human neurons is not well understood, we were interested in characterizing and defining a model system for IL-6-induced activation of signal transduct ion cascades, transcriptional activation, and protein synthesis in human ne uronal cells. We show that IL-6 leads to transcriptional activation of sign al transducer and activator of transcription 3 (STAT3) in human SH-SY5Y neu roblastoma cells. IL-6-induced activation and translocation of STAT3 and to a lesser degree STAT1 but not STAT5 are demonstrated. STAT3 is phosphoryla ted on Tyr(705) and Ser(727) residues on stimulation with IL-6, suggesting maximal activation of transcription. We also show IL-6-induced phosphorylat ion of p42/44 mitogen-activated protein (MAP) kinase, providing evidence fo r MAP kinase pathway activation. The physiological relevance of our results is confirmed by IL-6-induced phosphorylation of key signaling proteins of both STAT and MAP kinase pathway in rat primary hippocampal neurons. Furthe rmore, de novo protein synthesis on IL-6 activation is demonstrated.