title: The proinflammatory cytokine, interleukin-17A, augments mitochondrial function and neurite outgrowth of cultured adult sensory neurons derived from normal and diabetic rats.
abstract: BACKGROUND
  Diabetic neuropathy comprises dying back of nerve endings that reflects impairment in axonal plasticity and regenerative nerve growth. Metabolic changes in diabetes can lead to a dysregulation of hormonal mediators, such as cytokines, that may constrain distal nerve fiber growth. Interleukin-17 (IL-17A), a proinflammatory and neurotropic cytokine produced by T-cells, was significantly reduced in sciatic nerve of streptozotocin (STZ)-diabetic rats. Thus we studied the effect of IL-17A on the phenotype of sensory neurons derived from age matched control or type 1 diabetic rats. The aims were to determine the ability of IL-17A to enhance neurite outgrowth in cultured sensory neurons, investigate the signaling pathways activated by IL-17A, study the role of mitochondria and mechanistically link to neurite outgrowth.
  
  
  RESULTS
  IL-17A (10 ng/ml; p<0.05) significantly and dose-dependently increased total neurite outgrowth in cultures of adult dorsal root ganglia (DRG) sensory neurons derived from both control and streptozotocin (STZ)-diabetic rats. This enhancement was mediated by IL-17A-dependent activation of extracellular-regulated protein kinase (ERK) and phosphoinositide-3 kinase (PI-3K) signal transduction pathways. Pharmacological blockade of one of these activated pathways triggered complete inhibition of neurite outgrowth. IL-17A augmented mitochondrial bioenergetic function of sensory neurons derived from control or diabetic rats and this was also mediated via ERK or PI-3K. IL-17A-dependent elevation of bioenergetic function was associated with augmented expression of proteins of the mitochondrial electron transport system complexes.
  
  
  CONCLUSIONS
  IL-17A enhanced axonal plasticity through activation of ERK and PI-3K pathways and was associated with augmented mitochondrial bioenergetic function in sensory neurons.
authors: Division of Neurodegenerative Disorders, St Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada; Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, MB R3E 0T6, Canada.
authors: Tarek
authors: T
authors: Habash
authors: Division of Neurodegenerative Disorders, St Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada.
authors: Ali
authors: A
authors: Saleh
authors: Division of Neurodegenerative Disorders, St Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada.
authors: Subir K
authors: SK
authors: Roy Chowdhury
authors: Division of Neurodegenerative Disorders, St Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada.
authors: Darrell R
authors: DR
authors: Smith
authors: Division of Neurodegenerative Disorders, St Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada; Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, MB R3E 0T6, Canada. Electronic address: pfernyhough@sbrc.ca.
authors: Paul
authors: P
authors: Fernyhough
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000473:pathology*; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005727:Ganglia, Spinal / Q000473:pathology; D020381:Interleukin-17 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D009025:Morpholines / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism; D016501:Neurites / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000473:pathology*; D013311:Streptozocin / Q000633:toxicity
chemical_list: D000903:Antibiotics, Antineoplastic; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D020381:Interleukin-17; D009025:Morpholines; D009097:Multienzyme Complexes; D009570:Nitriles; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D013311:Streptozocin; D003576:Electron Transport Complex IV
keywords: Bioenergetics; Diabetes; Nerve regeneration; Neuropathy; Neurotrophic factors; Peripheral nerve