Over-Expression of Pancreatic Pituitary Adenylate Cyclase–Activating Polypeptide (PACAP) Aggravates Cerulein-Induced Acute Pancreatitis in Mice

Ken-ichi Hamagami; Yusuke Sakurai; Norihito Shintani; Naoko Higuchi; Kazuya Ikeda; Hitoshi Hashimoto; Akinobu Suzuki; Hiroshi Kiyama; Akemichi Baba

doi:10.1254/jphs.09119FP

Full Papers

Over-Expression of Pancreatic Pituitary Adenylate Cyclase–Activating Polypeptide (PACAP) Aggravates Cerulein-Induced Acute Pancreatitis in Mice

Ken-ichi Hamagami, Yusuke Sakurai, Norihito Shintani, Naoko Higuchi, Kazuya Ikeda, Hitoshi Hashimoto, Akinobu Suzuki, Hiroshi Kiyama, Akemichi Baba

Author information

Ken-ichi Hamagami
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan
Yusuke Sakurai
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan
Norihito Shintani
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan
Naoko Higuchi
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan
Kazuya Ikeda
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan
Hitoshi Hashimoto
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan
Center for Child Mental Development, Graduate School of Medicine, Osaka University, Japan
Akinobu Suzuki
Department of Anatomy & Neurobiology, Graduate School of Medicine, Osaka City University, Japan
Hiroshi Kiyama
Department of Anatomy & Neurobiology, Graduate School of Medicine, Osaka City University, Japan
Akemichi Baba
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Japan

Keywords: pituitary adenylate cyclase–activating polypeptide (PACAP), cerulein, acute pancreatitis, regenerating gene III β (RegIIIβ)

JOURNAL FREE ACCESS

2009 Volume 110 Issue 4 Pages 451-458

DOI https://doi.org/10.1254/jphs.09119FP

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Abstract

Development of human chronic pancreatitis is associated with intrapancreatic accumulation of pituitary adenylate cyclase–activating polypeptide (PACAP) accompanied with an altered inflammatory response (Michalski et al., Am J Physiol Gastrointest Liver Physiol. 2008;294:G50–G57). To investigate the role of pancreatic PACAP in the development of acute pancreatitis, we employed transgenic mice over-expressing PACAP in pancreatic β-cells (PACAP-Tg). In comparison to wild-type mice, PACAP-Tg mice exhibited more severe pathophysiological signs of the cerulein-induced pancreatitis at 12 h, as evidenced by higher serum amylase and lipase levels accompanied by the exacerbation of pancreatic edema, necrosis, and inflammation. Cerulein treatment increased mRNA expression of several proinflammatory cytokines (TNFα, IL-1β, and IL-6) at 12 h with similar magnitude both in wild-type and PACAP-Tg mice. In addition, the mRNA and protein levels of regenerating gene III β (RegIIIβ), a key factor in the pancreatic response to acute pancreatitis, were up-regulated at 24 h in wild-type mice upon cerulein administration, whereas they were attenuated in PACAP-Tg mice. These data indicate that over-expressed PACAP in pancreas enhances the cerulein-induced inflammatory response of both acinar cells, leading to aggravated acute pancreatitis, which was accompanied by a down-regulation of RegIIIβ, an anti-inflammatory factor.

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