Neuroprotection by Interleukin-6 Is Mediated by Signal Transducer and Activator of Transcription 3 and Antioxidative Signaling in Ischemic Stroke
Background and Purpose—Interleukin-6 (IL-6) has been shown to have a neuroprotective effect in brain ischemic injury. However, its molecular mechanisms are still poorly understood. In this study, we investigated the neuroprotective role of the IL-6 receptor (IL-6R) by IL-6 in the reactive oxygen species defense system after transient focal cerebral ischemia (tFCI).
Methods—IL-6 was injected in mice before and after middle cerebral artery occlusion. Coimmunoprecipitation assays were performed for analysis of an IL-6R association after tFCI. Primary mouse cerebral cortical neurons were transfected with small interfering RNA probes targeted to IL-6Rα or gp130 and were used for chromatin-immunoprecipitation assay, luciferase promoter assay, and cell viability assay. Reduction in infarct volumes by IL-6 was measured after tFCI.
Results—IL-6R was disrupted through a disassembly between IL-6Rα and gp130 associated by protein oxidation after reperfusion after tFCI. This suppressed phosphorylation of signal transducer and activator of transcription 3 (STAT3) and finally induced neuronal cell death through a decrease in manganese–superoxide dismutase. However, IL-6 injections prevented disruption of IL-6R against reperfusion after tFCI, consequently restoring activity of STAT3 through recovery of the binding of STAT3 to gp130. Moreover, IL-6 injections restored the transcriptional activity of the manganese–superoxide dismutase promoter through recovery of the recruitment of STAT3 to the manganese–superoxide dismutase promoter and reduced infarct volume after tFCI.
Conclusions—This study demonstrates that IL-6 has a neuroprotective effect against cerebral ischemic injury through IL-6R-mediated STAT3 activation and manganese–superoxide dismutase expression.
- Received May 19, 2011.
- Revision received June 28, 2011.
- Accepted July 12, 2011.
- © 2011 American Heart Association, Inc.