Abstract
BackgroundThe 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 FindingsMice 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/SignificanceSynthetic 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.
Highlights
Pituitary adenylate cyclase-activating polypeptide (PACAP) was first identified as a hypothalamic neuropeptide stimulating adenylate cyclase activity in the pituitary gland [1]
Whereas control mice suffered from acute pan-ileitis with necroses at day 7 p.i. and succumbed to infection, PACAP treated mice were protected from ileal immunopathology in a time-of-treatment dependent manner as indicated by better clinical conditions, macroscopic aspects and only minor small intestinal mucosal changes with preserved epithelial lining due to PACAP prophylaxis
Our results are supported by two previous studies demonstrating that DSSinduced colitis was exacerbated in PACAP2/2 mice [8,9], whereas the devastating phenotype could be rescued by intraperitoneal synthetic PACAP administration at day 1 following colitis induction [9]
Summary
Pituitary adenylate cyclase-activating polypeptide (PACAP) was first identified as a hypothalamic neuropeptide stimulating adenylate cyclase activity in the pituitary gland [1]. Besides the central nervous system, PACAP is widely expressed in peripheral organs of the endocrine, reproductive, respiratory, and digestive system as well as in lymphoid organs including immune cells [2]. PACAP exerts its immunemodulatory functions following binding on three receptors. VIP and PACAP, can bind to VPAC1 and VPAC2 receptors present on immune cells such as lymphocytes and macrophages, PAC1 comprises a receptor specific for PACAP, which is expressed by macrophages but not lymphocytes [3,4,5]. In experimental trinitrobenzene sulfonic acid (TNBS) induced colitis, VIP exerted prophylactic and therapeutic effects [10], providing evidence for antiinflammatory effects of PACAP and VIP in the intestinal tract. The neuropeptide Pituitary adenylate cyclase-activating polypeptide (PACAP) plays pivotal roles in immunity and inflammation. Potential immune-modulatory properties of PACAP have not been investigated in experimental ileitis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
