title: Interleukin-6 induces proliferation in adult spinal cord-derived neural progenitors via the JAK2/STAT3 pathway with EGF-induced MAPK phosphorylation.
abstract: BACKGROUND
  In a previous study, we observed cell proliferation 3 days after spinal cord injury, and levels of interleukin-6 (IL-6) and epidermal growth factor (EGF) had significantly increased in the region of the injury.
  
  
  OBJECTIVE
  The purpose of the new study described here was to evaluate the roles of IL-6 and EGF after traumatic damage to the spinal cord having isolated neural progenitor cells (NPC) from adult mice.
  
  
  RESULTS
  Evidence provided by the trypan blue dye exclusion assay, 5-bromodeoxyuridine immunoreactivity and Western blot analysis indicated that IL-6 and EGF induced proliferation of these spinal cord-derived NPCs via phosphorylation of Janus-activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinases (MAPK), respectively. Combined treatment with IL-6 and EGF accelerated proliferation of cells synergistically and phosphorylation of STAT3 and extracellular signal-regulated kinase 1/2 (Erk1/2). Furthermore, AG490 and AG1478, JAK2 inhibitor and EGFR inhibitor, respectively, prevented the IL-6- and EGF-induced proliferation of the cells. Interestingly, IL-6-activated MAPKs but EGF did not influence JAK2/STAT3 activation; AG490 specifically inhibited IL-6-induced Erk1/2 phosphorylation without affecting IL-6-induced phosphorylation of Raf and MEK1/2. These results indicate that IL-6 is directly involved in Erk1/2 activation via JAK2 and that Erk1/2 provides a signal bridge between the IL-6-induced JAK2/STAT3 pathway and EGF-induced MAPK pathway.
  
  
  CONCLUSIONS
  Our study is the first demonstration of IL-6- and EGF-stimulated proliferation of spinal cord progenitor cells via JAK2/STAT3 and MAPK signalling pathways. These pathways play key roles in repopulation and regeneration of spinal cord tissue after injury. It may represent novel therapeutic targets for pharmacological intervention in central nervous system disease, including spinal cord injury.
authors.affiliation: Department of Physiology, College of Medicine, Pusan National University, Ami-Dong, Seo-Gu, Busan, South Korea.
authors.forename: M K
authors.initials: MK
authors.lastname: Kang
authors.forename: S K
authors.initials: SK
authors.lastname: Kang
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D001973:Bromodeoxyuridine