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

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

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 7

Inhibition of the protective effect of PAP1 using PAP1 knockdown in vivo.

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Inhibition of the protective effect of PAP1 using PAP1 knockdown in vivo...
(A) Three age- and sex-matched relaflox/flox mice were injected with SDI or PAP1 siRNA (PAP1 90 and PAP1 288) twice in an 18-hour interval (circles) and then were subjected to cerulein-induced pancreatitis (arrows). (B) Pancreatic homogenates from mice as in A were obtained and immunoblotted for PAP1. Blotting for ERK1/2 protein was used as a loading control. (C) relaflox/flox mice were pretreated with specific and nonspecific siRNA as in A and subsequently injected with 1 i.p. dose of 50 μg/kg cerulein. One hour after injection, pancreatic nuclear protein extracts (10 μg) were subjected to gel retardation assays with an NF-κB consensus probe. (D) Representative H&E staining of pancreata from mice treated as in A. Note the increase in infiltration and massive necrosis in mice with PAP1 knockdown. (E and F) Pancreatic injury was measured by determining the enzyme activity of MPO in the pancreas (E) and LDH in the serum (F). Values are mean ± SD for independent animals (n = 3). *P < 0.05.