Phospholipases A-II (PLA2-II) induces acute pancreatitis through activation of the transcription factor NF-kappaB

M.-s. Zhang, K.-j. Zhang, J. Zhang, X.-l. Jiao, D. Chen, D.-l. Zhang

General Surgery, the Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shangdong, China. phdzdl@yahoo.com

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• Gastroenterology

OBJECTIVES: Acute pancreatitis (AP) is an inflammatory disease of the pancreas characterized by local inflammation. Secretory phospholipases A-II (sPLA2-II) have been implicated in triggering AP, but their exact role to evoke AP is largely unknown. NF-kB activation has previously been shown to induce acute pancreatitis. The aim of this study is to explore that PLA2-II triggers AP by activation of NF-kB and the expression of inducible inflammatory mediators.

MATERIALS AND METHODS: Acute pancreatitis in vivo was induced in Wistar rats by retrograde infusion of 4% sodium taurocholate (TAC) into the pancreatic duct. Then the Wistar rats were devided into 2 groups: (1) PLA2 II-specific siRNA was subsequently administrated subcapsularly after infusion of TAC. (2) One hour before the intraductal injection of TCA, the rats were treated with PDTC 100 mg/kg twice i.p. in 1 h interval. Induction of pancreatitis was confirmed by histopathology, NF-kB activity and expression in pancreas was detected by EMSA and immunohistochemistry. Inflammatory mediators such as the tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1beta, intercellular adhesion molecule-1 (ICAM-1), IL-6 and IL-8 in blood was detected by ELISA. The severity of the disease and the mortality were observed.

RESULTS: We demonstrated that TAC specifically induces pancreatitis, induces PLA2-II expression and activates NF-kappaB and proinflammatory cytokine synthesis in the pancreas of rats. sPLA2-II siRNA transfection blocked NF-kappaB activation and proinflammatory cytokine expression and relieved pancreatitis severity. PDTC treatment blocked NF-kappaB activation and proinflammatory cytokine expression. Pretreatment with PDTC or PLA2 II-specific siRNA transfection improved the survival of the rats.

CONCLUSIONS: These findings suggest that PLA2-II induces acute pancreatitis through activation of the transcription factor NF-kappaB. siRNA mediated gene knockdown of PLA2-II relieves pancreatitis severity at least partly mediated by the inhibition of NF-kappaB activation and proinflammatory cytokine synthesis.

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