title: Deletion of IκBα activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A.
abstract: OBJECTIVE
  The transcription factor nuclear factor-κB (NF-κB) (a heterodimer of NF-κB1p50 and RelA) is activated rapidly in acute pancreatitis (AP). However, it is not clear whether NF-κB promotes or protects against AP. We used the NF-κB inhibitor protein, inhibitor of κB (IκB)α, to study the roles of NF-κB in the development of AP in mice.
  
  
  METHODS
  IκBα or the combination of IκBα and RelA selectively were deleted from pancreas of mice using the Cre/locus of cross-over P strategy; cerulein or L-arginine were used to induce AP. We performed microarray analyses of the IκBα- and RelA-deficient pancreata. DNA from healthy individuals and patients with acute or chronic pancreatitis were analyzed for variants in coding regions of alpha-1-antichymotrypsin.
  
  
  RESULTS
  Mice with pancreas-specific deletion of IκBα had constitutive activation of RelA and a gene expression profile consistent with NF-κB activation; development of AP in these mice was attenuated and trypsin activation was impaired. However, AP was fully induced in mice with pancreas-specific deletion of IκBα and RelA. By using genome-wide expression analysis, we identified a cluster of NF-κB-regulated genes that might protect against the development of AP. The serine protease inhibitor 2A (Spi2a) was highly up-regulated in IκBα-deficient mice. Lentiviral-mediated expression of Spi2A reduced the development of AP in C57BL/6 and RelA-deficient mice. However, we did not correlate any variants of alpha-1-antichymotrypsin, the human homologue of Spi2a, with acute or chronic pancreatitis.
  
  
  CONCLUSIONS
  Pancreas-specific deletion of IκBα results in nuclear translocation of RelA and reduces AP induction and trypsin activation in mice after administration of cerulein or L-arginine. Constitutive activation of RelA up-regulates Spi2A, which protects mice against the development of AP.
authors.affiliation: II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität Munich, Munich, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Neuhöfer
authors.forename: Song
authors.initials: S
authors.lastname: Liang
authors.forename: Henrik
authors.initials: H
authors.lastname: Einwächter
authors.forename: Christiane
authors.initials: C
authors.lastname: Schwerdtfeger
authors.forename: Thomas
authors.initials: T
authors.lastname: Wartmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Treiber
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schulz
authors.forename: Karen
authors.initials: K
authors.lastname: Dlubatz
authors.forename: Marina
authors.initials: M
authors.lastname: Lesina
authors.forename: Kalliope N
authors.initials: KN
authors.lastname: Diakopoulos
authors.forename: Sonja
authors.initials: S
authors.lastname: Wörmann
authors.forename: Walter
authors.initials: W
authors.lastname: Halangk
authors.forename: Heiko
authors.initials: H
authors.lastname: Witt
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Hana
authors.initials: H
authors.lastname: Algül
mesh_terms: D061354:Acinar Cells; D000818:Animals; D001120:Arginine; D002108:Ceruletide; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005822:Genetic Vectors; D005838:Genotype; D020672:I-kappa B Proteins / Q000235:genetics* / Q000378:metabolism; D016086:Lentivirus; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010179:Pancreas / Q000201:enzymology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D015843:Serpins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism; D015854:Up-Regulation; D000514:alpha 1-Antichymotrypsin / Q000235:genetics*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D009687:Nuclear Proteins; C498144:Rela protein, mouse; C490400:Serpina3k protein, mouse; D015843:Serpins; D051996:Transcription Factor RelA; D000514:alpha 1-Antichymotrypsin; D000072000:NF-KappaB Inhibitor alpha; D002108:Ceruletide; D001120:Arginine; D014357:Trypsin