title: The cytokine tumor necrosis factor-like weak inducer of apoptosis and its receptor fibroblast growth factor-inducible 14 have a neuroprotective effect in the central nervous system.
abstract: BACKGROUND
  Cerebral cortical neurons have a high vulnerability to the harmful effects of hypoxia. However, the brain has the ability to detect and accommodate to hypoxic conditions. This phenomenon, known as preconditioning, is a natural adaptive process highly preserved among species whereby exposure to sub-lethal hypoxia promotes the acquisition of tolerance to a subsequent lethal hypoxic injury. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are found in neurons and their expression is induced by exposure to sub-lethal hypoxia. Accordingly, in this work we tested the hypothesis that the interaction between TWEAK and Fn14 induces tolerance to lethal hypoxic and ischemic conditions.
  
  
  METHODS
  Here we used in vitro and in vivo models of hypoxic and ischemic preconditioning, an animal model of transient middle cerebral artery occlusion and mice and neurons genetically deficient in TWEAK, Fn14, or tumor necrosis factor alpha (TNF-α) to investigate whether treatment with recombinant TWEAK or an increase in the expression of endogenous TWEAK renders neurons tolerant to lethal hypoxia. We used enzyme-linked immunosorbent assay to study the effect of TWEAK on the expression of neuronal TNF-α, Western blot analysis to investigate whether the effect of TWEAK was mediated by activation of mitogen-activated protein kinases and immunohistochemical techniques and quantitative real-time polymerase chain reaction analysis to study the effect of TWEAK on apoptotic cell death.
  
  
  RESULTS
  We found that either treatment with recombinant TWEAK or an increase in the expression of TWEAK and Fn14 induce hypoxic and ischemic tolerance in vivo and in vitro. This protective effect is mediated by neuronal TNF-α and activation of the extracellular signal-regulated kinases 1 and 2 pathway via phosphorylation and inactivation of the B-cell lymphoma 2-associated death promoter protein.
  
  
  CONCLUSIONS
  Our work indicate that the interaction between TWEAK and Fn14 triggers the activation of a cell signaling pathway that results in the induction of tolerance to lethal hypoxia and ischemia. These data indicate that TWEAK may be a potential therapeutic strategy to protect the brain from the devastating effects of an ischemic injury.
authors.affiliation: Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Echeverry
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.forename: Woldeab B
authors.initials: WB
authors.lastname: Haile
authors.forename: Jialing
authors.initials: J
authors.lastname: Wu
authors.forename: Manuel
authors.initials: M
authors.lastname: Yepes
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000188:drug therapy; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology*; D019194:Ischemic Preconditioning / Q000379:methods*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000378:metabolism*; D000074050:TWEAK Receptor; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000074049:Cytokine TWEAK; D018696:Neuroprotective Agents; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D005947:Glucose