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PLoS One. 2014 Sep 19;9(9):e108389. doi: 10.1371/journal.pone.0108389. eCollection 2014.

Pituitary adenylate cyclase-activating polypeptide ameliorates experimental acute ileitis and extra-intestinal sequelae.

Author information

1
Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
2
Department of Microbiology and Hygiene, University of Magdeburg, Magdeburg, Germany.
3
Department of Medicine I for Gastroenterology, Infectious Disease and Rheumatology/Research Center ImmunoSciences (RCIS), Charité - University Medicine Berlin, Berlin, Germany.
4
Department of Anatomy, PTE-MTA Lendület PACAP Research Team, University of Pecs, Pecs, Hungary.
5
Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
6
Department and Clinic of Surgery and Ophthalmology, Faculty of Veterinary Medicine, Szent Istvan University Budapest, Budapest, Hungary.

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.

METHODOLOGY/PRINCIPAL FINDINGS:

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.

CONCLUSION/SIGNIFICANCE:

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.

PMID:
25238233
PMCID:
PMC4169633
DOI:
10.1371/journal.pone.0108389
[Indexed for MEDLINE]
Free PMC Article

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