title: Interleukin-17 sensitizes joint nociceptors to mechanical stimuli and contributes to arthritic pain through neuronal interleukin-17 receptors in rodents.
abstract: OBJECTIVE
  Interleukin-17 (IL-17) is considered a proinflammatory cytokine, but whether neuronal IL-17 receptors contribute to the generation of arthritic pain is unknown. This study was undertaken to explore whether IL-17A acts on neurons, whether it sensitizes joint nociceptors, and whether neutralization of IL-17 is antinociceptive.
  
  
  METHODS
  We recorded action potentials from rat joint nociceptors after intraarticular injection of IL-17A. We studied the expression of the IL-17A receptor in the rat dorsal root ganglia (DRG), explored the effect of IL-17A on signaling pathways in cultured rat DRG neurons, and using patch clamp recordings, monitored changes of excitability by IL-17A. We tested whether an antibody to IL-17 influences pain behaviors in mice with antigen-induced arthritis (AIA).
  
  
  RESULTS
  A single injection of IL-17A into the rat knee joint elicited a slowly developing and long-lasting sensitization of nociceptive C fibers of the joint to mechanical stimuli, which was not attenuated by neutralizing tumor necrosis factor α or IL-6. The IL-17A receptor was visualized in most rat DRG neurons, the cell bodies of primary sensory neurons. In isolated and cultured rat DRG neurons, IL-17A caused rapid phosphorylation of protein kinase B and ERK, and it rapidly enhanced excitability. In mice with unilateral AIA in the knee, an antibody against IL-17 improved the guarding score and reduced secondary mechanical hyperalgesia at the ipsilateral paw.
  
  
  CONCLUSIONS
  Our findings indicate that IL-17A has the potential to act as a pain mediator by targeting IL-17 receptors in nociceptive neurons, and these receptors are particularly involved in inflammation-evoked mechanical hyperalgesia.
authors.affiliation: Institute of Physiology I/Neurophysiology, Jena University Hospital-Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Richter
authors.forename: Gabriel
authors.initials: G
authors.lastname: Natura
authors.forename: Matthias
authors.initials: M
authors.lastname: Ebbinghaus
authors.forename: Gisela Segond
authors.initials: GS
authors.lastname: von Banchet
authors.forename: Susanne
authors.initials: S
authors.lastname: Hensellek
authors.forename: Christian
authors.initials: C
authors.lastname: König
authors.forename: Rolf
authors.initials: R
authors.lastname: Bräuer
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Schaible
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000941:Antigens / Q000009:adverse effects; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006930:Hyperalgesia / Q000503:physiopathology*; D007270:Injections, Intra-Articular; D020381:Interleukin-17 / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D007719:Knee Joint / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology*; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053722:Receptors, Interleukin-17 / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases