title: Neuroprotection by interleukin-6 is mediated by signal transducer and activator of transcription 3 and antioxidative signaling in ischemic stroke.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, 1201 Welch Road, MSLS #P314, Stanford, CA 94305-5487, USA.
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.forename: Gab Seok
authors.initials: GS
authors.lastname: Kim
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: C494199:IL6ST protein, human; D015850:Interleukin-6; D018696:Neuroprotective Agents; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130; D013482:Superoxide Dismutase