title: Activation of colo-rectal high-threshold afferent nerves by Interleukin-2 is tetrodotoxin-sensitive and upregulated in a mouse model of chronic visceral hypersensitivity.
abstract: BACKGROUND
  Chronic visceral pain is a defining feature of irritable bowel syndrome (IBS). IBS patients often show alterations in innate and adaptive immune function which may contribute to symptoms. Immune mediators are known to modulate the activity of viscero-sensory afferent nerves, but the focus has been on the innate immune system. Interleukin-2 (IL-2) is primarily associated with adaptive immune responses but its effects on colo-rectal afferent function in health or disease are unknown.
  
  
  METHODS
  Myeloperoxidase (MPO) activity determined the extent of inflammation in health, acute trinitrobenzene-sulfonic acid (TNBS) colitis, and in our post-TNBS colitis model of chronic visceral hypersensitivity (CVH). The functional effects of IL-2 on high-threshold colo-rectal afferents and the expression of IL-2R and NaV 1.7 mRNA in colo-rectal dorsal root ganglia (DRG) neurons were compared between healthy and CVH mice.
  
  
  RESULTS
  MPO activity was increased during acute colitis, but subsided to levels comparable to health in CVH mice. IL-2 caused direct excitation of colo-rectal afferents that was blocked by tetrodotoxin. IL-2 did not affect afferent mechanosensitivity in health or CVH. However, an increased proportion of afferents responded directly to IL-2 in CVH mice compared with controls (73% vs 33%; p < 0.05), and the abundance of IL-2R and NaV 1.7 mRNA was increased 3.5- and 2-fold (p < 0.001 for both) in colo-rectal DRG neurons.
  
  
  CONCLUSIONS
  IL-2, an immune mediator from the adaptive arm of the immune response, affects colo-rectal afferent function, indicating these effects are not restricted to innate immune mediators. Colo-rectal afferent sensitivity to IL-2 is increased long after healing from inflammation.
authors.affiliation: Centre for Nutritional and Gastrointestinal Diseases, Department of Medicine, University of Adelaide and South Australian Health Medical Health Research Institute, Adelaide, SA, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Campaniello
authors.affiliation: Centre for Nutritional and Gastrointestinal Diseases, Department of Medicine, University of Adelaide and South Australian Health Medical Health Research Institute, Adelaide, SA, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Harrington
authors.affiliation: Centre for Nutritional and Gastrointestinal Diseases, Department of Medicine, University of Adelaide and South Australian Health Medical Health Research Institute, Adelaide, SA, Australia.
authors.forename: C M
authors.initials: CM
authors.lastname: Martin
authors.affiliation: Neurogastroenterology Group, Blizard Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Ashley Blackshaw
authors.affiliation: Centre for Nutritional and Gastrointestinal Diseases, Department of Medicine, University of Adelaide and South Australian Health Medical Health Research Institute, Adelaide, SA, Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Brierley
authors.affiliation: Centre for Nutritional and Gastrointestinal Diseases, Department of Medicine, University of Adelaide and South Australian Health Medical Health Research Institute, Adelaide, SA, Australia.
authors.forename: P A
authors.initials: PA
authors.lastname: Hughes
mesh_terms: D056704:Adaptive Immunity; D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006930:Hyperalgesia / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D007376:Interleukin-2 / Q000494:pharmacology*; D043183:Irritable Bowel Syndrome / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D059265:Visceral Pain / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology
chemical_list: D007376:Interleukin-2; D062556:NAV1.7 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; C503479:Scn9a protein, mouse; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase
keywords: colitis; cytokine; inflammation; irritable bowel syndrome; pain