title: Increased prokineticin 2 expression in gut inflammation: role in visceral pain and intestinal ion transport.
abstract: BACKGROUND
  Prokineticin 2 (PROK2) is an inflammatory cytokine-like molecule expressed predominantly by macrophages and neutrophils infiltrating sites of tissue damage. Given the established role of prokineticin signaling on gastrointestinal function, we have explored Prok2 gene expression in inflammatory conditions of the gastrointestinal tract and assessed the possible consequences on gut physiology.
  
  
  METHODS
  Prokineticin expression was examined in normal and colitic tissues using qPCR and immunohistochemistry. Functional responses to PROK2 were studied using calcium imaging and a novel antagonist, Compound 3, used to determine the role of PROK2 and prokineticin receptors in inflammatory visceral pain and ion transport.
  
  
  RESULTS
  Prok2 gene expression was up-regulated in biopsy samples from ulcerative colitis patients, and similar elevations were observed in rodent models of inflammatory colitis. Prokineticin receptor 1 (PKR1) was localized to the enteric neurons and extrinsic sensory neurons, whereas Pkr2 expression was restricted to sensory ganglia. In rats, PROK2-increased intracellular calcium levels in cultured enteric and dorsal root ganglia neurons, which was blocked by Compound 3. Moreover, PROK2 acting at prokineticin receptors stimulated intrinsic neuronally mediated ion transport in rat ileal mucosa. In vivo, Compound 3 reversed intracolonic mustard oil-induced referred allodynia and TNBS-induced visceral hypersensitivity, but not non-inflammatory, stress-induced visceral pain.
  
  
  CONCLUSIONS
  Elevated Prok2 levels, as a consequence of gastrointestinal tract inflammation, induce visceral pain via prokineticin receptors. This observation, together with the finding that PROK2 can modulate intestinal ion transport, raises the possibility that inhibitors of PROK2 signaling may have clinical utility in gastrointestinal disorders, such as irritable bowel syndrome and inflammatory bowel disease.
authors: Novartis Institutes for Biomedical Research, Novartis Horsham Research Centre, Horsham, West Sussex, UK.
authors: Robert P
authors: RP
authors: Watson
authors: Elliot
authors: E
authors: Lilley
authors: Moh
authors: M
authors: Panesar
authors: Gurdip
authors: G
authors: Bhalay
authors: Steven
authors: S
authors: Langridge
authors: Shin-Shay
authors: SS
authors: Tian
authors: Conor
authors: C
authors: McClenaghan
authors: Anna
authors: A
authors: Ropenga
authors: Fanning
authors: F
authors: Zeng
authors: Mark S
authors: MS
authors: Nash
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003092:Colitis / Q000378:metabolism / Q000473:pathology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000033:anatomy & histology / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism*; D017136:Ion Transport / Q000502:physiology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism; D059265:Visceral Pain / Q000503:physiopathology*
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human; C486586:Prok2 protein, mouse; D043562:Receptors, G-Protein-Coupled; C513686:prokineticin 2, rat; D002118:Calcium