title: Phospholipases A-II (PLA2-II) induces acute pancreatitis through activation of the transcription factor NF-kappaB.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: General Surgery, the Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shangdong, China. phdzdl@yahoo.com.
authors.forename: M-S
authors.initials: MS
authors.lastname: Zhang
authors.forename: K-J
authors.initials: KJ
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: X-L
authors.initials: XL
authors.lastname: Jiao
authors.forename: D
authors.initials: D
authors.lastname: Chen
authors.forename: D-L
authors.initials: DL
authors.lastname: Zhang
mesh_terms: D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D054501:Group II Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000097:blood; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010195:Pancreatitis / Q000097:blood / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D011759:Pyrrolidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage; D017208:Rats, Wistar; D012720:Severity of Illness Index; D015398:Signal Transduction; D013656:Taurocholic Acid; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors
chemical_list: D018836:Inflammation Mediators; D016328:NF-kappa B; D011759:Pyrrolidines; D034741:RNA, Small Interfering; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D013656:Taurocholic Acid; D054501:Group II Phospholipases A2