title: Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice.
abstract: OBJECTIVE
  Nuclear factor-κB (NF-κB) is activated during early stages of pancreatitis. This transcription factor regulates genes that control many cell activities, including inflammation and survival. There is evidence that activation of NF-κB protects against pancreatitis, and, in other cases, that it promotes this disease. We compared the effects of NF-κB in different mouse models of pancreatitis to understand these complications.
  
  
  METHODS
  To model constitutive activation of NF-κB, we expressed a transgene that encodes its p65 subunit or the inhibitor of κB kinase (IKK)2 in pancreatic acinar cells of mice. We analyzed effects on pancreatic tissues and levels of NF-κB target genes in these mice and compared them with mice that did not express transgenic p65 or IKK2 (controls).
  
  
  RESULTS
  Transgenic expression of p65 led to compensatory expression of the inhibitory subunit IKB-α and, therefore, no clear phenotype. However, p65 transgenic mice given injections of cerulein, to induce acute pancreatitis, had higher levels of NF-κB activity in acinar cells, greater levels of inflammation, and more severe outcomes than control mice. In contrast, constitutive expression of IKK2 directly increased the activity of NF-κB in acinar cells and induced pancreatitis. Prolonged activity of IKK2 (3 months) resulted in activation of stellate cells, loss of acinar cells, and fibrosis, which are characteristics of chronic pancreatitis. Co-expression of IKK2 and p65 greatly increased the expression of inflammatory mediators and the severity of pancreatitis, compared with control mice.
  
  
  CONCLUSIONS
  The level of NF-κB activation correlates with the severity of acute pancreatitis in mice. Longer periods of activation (3 months) lead to chronic pancreatitis. These findings indicate that strategies to inactivate NF-κB might be used to treat patients with acute or chronic pancreatitis.
authors.affiliation: Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Daniluk
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gaiser
authors.forename: Jun
authors.initials: J
authors.lastname: Chu
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Zhao-Shen
authors.initials: ZS
authors.lastname: Li
authors.forename: Craig D
authors.initials: CD
authors.lastname: Logsdon
authors.forename: Baoan
authors.initials: B
authors.lastname: Ji
mesh_terms: D061354:Acinar Cells / Q000378:metabolism*; D000818:Animals; D002108:Ceruletide; D004195:Disease Models, Animal; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D058954:Pancreatic Stellate Cells / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D012720:Severity of Illness Index; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D002108:Ceruletide; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse