title: Pituitary adenylate cyclase-activating polypeptide ameliorates experimental acute ileitis and extra-intestinal sequelae.
abstract: BACKGROUND
  The neuropeptide Pituitary adenylate cyclase-activating polypeptide (PACAP) plays pivotal roles in immunity and inflammation. So far, potential immune-modulatory properties of PACAP have not been investigated in experimental ileitis.
  
  
  RESULTS
  Mice were perorally infected with Toxoplasma (T.) gondii to induce acute ileitis (day 0) and treated daily with synthetic PACAP38 from day 1 to 6 post infection (p.i.; prophylaxis) or from day 4 to 6 p.i. (therapy). Whereas placebo-treated control mice suffered from acute ileitis at day 7 p.i. and succumbed to infection, intestinal immunopathology was ameliorated following PACAP prophylaxis. PACAP-treated mice exhibited increased abundance of small intestinal FOXP3+ cells, but lower numbers of ileal T lymphocytes, neutrophils, monocytes and macrophages, which was accompanied by less ileal expression of pro-inflammatory cytokines such as IL-23p19, IL-22, IFN-γ, and MCP-1. Furthermore, PACAP-treated mice displayed higher anti-inflammatory IL-4 concentrations in mesenteric lymph nodes and liver and higher systemic anti-inflammatory IL-10 levels in spleen and serum as compared to control animals at day 7 p.i. Remarkably, PACAP-mediated anti-inflammatory effects could also be observed in extra-intestinal compartments as indicated by reduced pro-inflammatory mediator levels in spleen (TNF-α, nitric oxide) and liver (TNF-α, IFN-γ, MCP-1, IL-6) and less severe histopathological sequelae in lungs and kidneys following prophylactic PACAP treatment. Strikingly, PACAP prolonged survival of T. gondii infected mice in a time-of-treatment dependent manner.
  
  
  CONCLUSIONS
  Synthetic PACAP ameliorates acute small intestinal inflammation and extra-intestinal sequelae by down-regulating Th1-type immunopathology, reducing oxidative stress and up-regulating anti-inflammatory cytokine responses. These findings provide novel potential treatment options of inflammatory bowel diseases.
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Heimesaat
authors.affiliation: Department of Microbiology and Hygiene, University of Magdeburg, Magdeburg, Germany.
authors.forename: Ildiko R
authors.initials: IR
authors.lastname: Dunay
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schulze
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Grundmann
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Alutis
authors.affiliation: Department of Medicine I for Gastroenterology, Infectious Disease and Rheumatology/Research Center ImmunoSciences (RCIS), Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Department of Anatomy, PTE-MTA Lendület PACAP Research Team, University of Pecs, Pecs, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tamas
authors.affiliation: Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
authors.forename: Gabor
authors.initials: G
authors.lastname: Toth
authors.affiliation: Department and Clinic of Surgery and Ophthalmology, Faculty of Veterinary Medicine, Szent Istvan University Budapest, Budapest, Hungary.
authors.forename: Miklos P
authors.initials: MP
authors.lastname: Dunay
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Ulf B
authors.initials: UB
authors.lastname: Göbel
authors.affiliation: Department of Anatomy, PTE-MTA Lendület PACAP Research Team, University of Pecs, Pecs, Hungary.
authors.forename: Dora
authors.initials: D
authors.lastname: Reglodi
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bereswill
mesh_terms: D000818:Animals; D007079:Ileitis / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D007111:Immunity, Cellular / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D059208:Parasite Load; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D014123:Toxoplasmosis / Q000188:drug therapy* / Q000473:pathology
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide