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Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis
Hana Algül, … , Stephan Paxian, Roland M. Schmid
Hana Algül, … , Stephan Paxian, Roland M. Schmid
Published June 1, 2007
Citation Information: J Clin Invest. 2007;117(6):1490-1501. https://doi.org/10.1172/JCI29882.
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Research Article Article has an altmetric score of 6

Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis

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Abstract

Activation of the transcription factor NF-κB/Rel has been shown to be involved in inflammatory disease. Here we studied the role of RelA/p65, the main transactivating subunit, during acute pancreatitis using a Cre-loxP strategy. Selective truncation of the rela gene in pancreatic exocrine cells led to both severe injury of the acinar cells and systemic complications including lung and liver damage. Our data demonstrated that expression and induction of the protective pancreas-specific acute phase protein pancreatitis-associated protein 1 (PAP1) depended on RelA/p65. Lentiviral gene transfer of PAP1 cDNA reduced the extent of necrosis and infiltration in the pancreata of mice with selective truncation of RelA/p65. These results provide in vivo evidence for RelA/p65 protection of acinar cell death via upregulation of PAP1. Moreover, our data underscore the pancreas-specific role of NF-κB/Rel and suggest multidimensional roles of NF-κB/Rel in different cells and contexts during inflammation.

Authors

Hana Algül, Matthias Treiber, Marina Lesina, Hassan Nakhai, Dieter Saur, Fabian Geisler, Alexander Pfeifer, Stephan Paxian, Roland M. Schmid

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Figure 1

Pancreas-specific truncation of RelA/p65 using a Cre-loxP system.

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Pancreas-specific truncation of RelA/p65 using a Cre-loxP system.
      ...
(A) Two identically oriented loxP sites (triangles) flank exons 7 and 10 of the rela gene. loxPmod, modified loxP site. (B) Recombination of genomic DNA from the pancreata of relaΔ/Δ mice was detected by Southern blot analysis using a probe external to the 5′ end of the targeting construct. No recombination was detected in the other organs. (C) Deletion of rela (exons 7–10) in the mouse pancreas was demonstrated at the protein level by Western blot of isolated acini from mice with the floxed allele in the presence or absence of Cre as indicated. In contrast to relaflox/flox mice, relaΔ/Δ mice display a truncated form of RelA/p65 (Δp65). Pancreas protein extracts (40 μg) were analyzed using antibodies against p50, IκBα, and β-actin (as a loading control). The protein marker (PM) indicates the size of detected protein bands.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 3 patents
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