title: Interleukin-6-dependent influence of nociceptive sensory neurons on antigen-induced arthritis.
abstract: BACKGROUND
  Interleukin-6 (IL-6) is an important mediator of inflammation. In addition to cells involved in inflammation, sensory nociceptive neurons express the IL-6 signal-transducer glycoprotein 130 (gp130). These neurons are not only involved in pain generation but also produce neurogenic inflammation by release of neuropeptides such as calcitonin gene-related peptide (CGRP). Whether IL-6 activation of sensory neurons contributes to the induction of inflammation is unknown. This study explored whether the action of IL-6 on sensory neurons plays a role in the generation of neurogenic inflammation and arthritis induction.
  
  
  METHODS
  In SNS-gp130(-/-) mice lacking gp130 selectively in sensory neurons and appropriate control littermates (SNS-gp130(flox/flox)), we induced antigen-induced arthritis (AIA), and assessed swelling, histopathological arthritis scores, pain scores, expression of CGRP in sensory neurons, serum concentrations of CGRP and cytokines, and the cytokine release from single cell suspensions from lymph nodes and spleens. In wild-type mice CGRP release was determined during development of AIA and, in cultured sensory neurons, upon IL-6 stimulation.
  
  
  RESULTS
  Compared to SNS-gp130(flox/flox) mice SNS-gp130(-/-) mice showed significantly weaker initial swelling, reduced serum concentrations of CGRP, IL-6, and IL-2, no inflammation-evoked upregulation of CGRP in sensory neurons, but similar histopathological arthritis scores during AIA. During the initial swelling phase of AIA, CGRP was significantly increased in the serum, knee and spleen. In vitro, IL-6 augmented the release of CGRP from cultured sensory neurons. Upon antigen-specific restimulation lymphocytes from SNS-gp130(-/-) mice released more interleukin-17 and interferon-γ than lymphocytes from SNS-gp130(flox/flox) mice. In naive lymphocytes from SNS-gp130(flox/flox) and SNS-gp130(-/-) mice CGRP reduced the release of IL-2 (a cytokine which inhibits the release of interleukin-17 and interferon-γ).
  
  
  CONCLUSIONS
  IL-6 signaling in sensory neurons plays a role in the expression of arthritis. Selective deletion of gp130 signaling in sensory neurons reduces the swelling of the joint (most likely by reducing neurogenic inflammation) but increases some proinflammatory systemic cellular responses such as the release of interleukin-17 and interferon-γ from lymphocytes upon antigen-specific restimulation. Thus IL-6 signaling in sensory neurons is not only involved in pain generation but also in the coordination of the inflammatory response.
authors.affiliation: Institute of Physiology I/Neurophysiology, Jena University Hospital - Friedrich Schiller University Jena, Teichgraben 8, 07740, Jena, Germany. matthias.ebbinghaus@med.uni-jena.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ebbinghaus
authors.affiliation: Institute of Physiology I/Neurophysiology, Jena University Hospital - Friedrich Schiller University Jena, Teichgraben 8, 07740, Jena, Germany. GISELA.SEGOND_VON_BANCHET@med.uni-jena.de.
authors.forename: Gisela
authors.initials: G
authors.lastname: Segond von Banchet
authors.affiliation: Institute of Physiology I/Neurophysiology, Jena University Hospital - Friedrich Schiller University Jena, Teichgraben 8, 07740, Jena, Germany. Julia.Massier@web.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Massier
authors.affiliation: Institute of Pathology, Jena University Hospital - Friedrich Schiller University Jena, Ziegelmühlenweg 1, 07740, Jena, Germany. Mieczyslaw.gajda@med.uni-jena.de.
authors.forename: Mieczyslaw
authors.initials: M
authors.lastname: Gajda
authors.affiliation: Institute of Pathology, Jena University Hospital - Friedrich Schiller University Jena, Ziegelmühlenweg 1, 07740, Jena, Germany. rolf.Braeuer@med.uni-jena.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bräuer
authors.affiliation: Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Fritz-Pregl-Strasse 3, 6020, Innsbruck, Austria. michaela.kress@i-med.ac.at.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kress
authors.affiliation: Institute of Physiology I/Neurophysiology, Jena University Hospital - Friedrich Schiller University Jena, Teichgraben 8, 07740, Jena, Germany. Hans-Georg.Schaible@med.uni-jena.de.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Schaible
mesh_terms: D000818:Animals; D000941:Antigens / Q000633:toxicity; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D050822:Cytokine Receptor gp130 / Q000172:deficiency; D005260:Female; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology
chemical_list: D000941:Antigens; C494200:Il6st protein, mouse; D015850:Interleukin-6; C577686:interleukin-6, mouse; D050822:Cytokine Receptor gp130