PACAP provides colonic protection against dextran sodium sulfate induced colitis

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) plays a crucial role in immunity and inflammation. Our aim was to obtain insight in the role of PACAP in experimental colitis in mice and thus its possible role in inflammatory bowel disease. PACAP-deficient (PACAP-/-) mice and wild-type control mice were challenged by colitis-inducing agent, dextran sulfate sodium (DSS). We monitored clinical symptoms, intestinal morphology, and difference of cytokine production in the proximal and distal colon. After DSS administration, mortality was more severe in PACAP-/- mice versus wild-type control mice. The histological score and the disease activity index of PACAP-/- mice were significantly higher than those of wild-type control mice. In proximal colon, production of IL-1beta and IL-6 in PACAP-/- mice were significantly upregulated on day 8 after DSS administration, compared to wild-type control mice. In distal colon, furthermore, production of IFNgamma, IL-1beta, IL-6, IL-12, and KC were significantly higher in PACAP-/- mice than in wild-type control mice on day 4. Our findings indicate that PACAP regulates the production of pro-inflammatory cytokine in the experimental colitis.

Protective Intestinal Effects of Pituitary Adenylate Cyclase Activating Polypeptide

“…However, histological scoring of the proximal and distal colon parts in DSS-induced colitis showed an increased number of infi ltrating cells and crypt damage in PACAPdefi cient mice. Furthermore, production of IL-1beta and IL-6 was upregulated by 50 % in the proximal colon of PACAP-defi cient mice, and that of IFN-gamma, IL-1beta, IL-6, IL-12, and keratinocyte-derived chemokine expression was upregulated in the distal colon by 50 % [ 95 ]. Conversely, levels of anti-infl ammatory cytokines such as IL-10 were only one third of that of wild type mice in the distal colon.…”

“…Two groups, independently of each other and at the same time, reported similar results in DSSinduced colonic infl ammation, a model of infl ammatory bowel disease [ 95 , 96 ]. Azuma and coworkers [ 95 ], using a 7-day exposure (short-term) to DSS, found that PACAP KO mice exhibited higher mortality (increased by about 50 %) and increased weight loss, bleeding and diarrhea, symptoms that are used to determine the disease activity index. The large intestines were more shortened in PACAP KO mice, to one third of wild type mice.…”

The Role of Interleukin-19 in Contact Hypersensitivity

“…Immunofluorescent staining was performed as described previously 20) with some modifications. 21) We used a rat anti-mouse F4/80 antibody (AbD Serotec, Oxford, U.K., CI:A3-1) to detect macrophages and a rat anti-mouse Gr-1 antibody (AbD Serotec, RB6-8C5) to detect neutrophils.…”

The selective PAC1 receptor agonist maxadilan inhibits neurogenic vasodilation and edema formation in the mouse skin

“…Besides its diverse effects in these organs, its inhibitory action on cellular and vascular components of inflammation and its vasodilatory actions have also been investigated in numerous studies (reviewed in: Vaudry et al, 2009). Anti-inflammatory properties of the peptide lead to its significant ameliorative effect in animal models of septic shock, stroke, diabetic nephropathy and colitis (Azuma et al, 2008;Banki et al, 2013;Dejda et al, 2011;Martinez et al, 2002). The effects of PACAP are mediated by G protein-coupled receptors: the specific PAC1 receptor with 8 different splice variants, and VPAC1 and VPAC2 receptors which bind PACAP and VIP with the same affinity (reviewed in: Vaudry et al, 2009).…”