Neuroprotection by interleukin-6 is mediated by signal transducer and activator of transcription 3 and antioxidative signaling in ischemic stroke

Stroke. 2011 Dec;42(12):3574-9. doi: 10.1161/STROKEAHA.111.626648. Epub 2011 Sep 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Cell Death / drug effects
  • Cytokine Receptor gp130 / metabolism
  • Interleukin-6 / metabolism
  • Interleukin-6 / pharmacology
  • Interleukin-6 / therapeutic use*
  • Male
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Phosphorylation / drug effects
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Stroke / drug therapy*
  • Stroke / metabolism
  • Superoxide Dismutase / metabolism


  • IL6ST protein, human
  • Interleukin-6
  • Neuroprotective Agents
  • STAT3 Transcription Factor
  • Cytokine Receptor gp130
  • Superoxide Dismutase