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.
View: Text | PDF
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

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

×

Figure 3

Pancreas-specific truncation of RelA/p65 exacerbates AP.

Options: View larger image (or click on image) Download as PowerPoint
Pancreas-specific truncation of RelA/p65 exacerbates AP. (A) relaflox/fl...
(A) relaflox/flox and relaΔ/Δ mice were given 8 hourly i.p. injections of cerulein (50 μg/kg) and sacrificed 8, 12, or 24 hours after the first injection. Histological sections of relaflox/flox and relaΔ/Δ mice were analyzed at the indicated time points. Note the increased vacuolization, morphologically apoptotic cells, ghost cells, edema, infiltration, and massive necrosis in the relaΔ/Δ pancreata. (B) Pancreatic injury was determined by measuring amylase and LDH enzyme activity in serum. Total tissue homogenates were obtained from pancreata of cerulein-injected mice at the indicated time points and subjected to trypsin activity analysis. Pancreatic edema was determined indirectly by increase in pancreatic weight. (C) H&E-stained pancreas sections from relaflox/flox and relaΔ/Δ mice 24 hours after cerulein-induced inflammation were used to measure and quantify necrotic parenchymal surface area. TUNEL assay results are expressed as the apoptotic index of pancreata from mice with AP. Apoptotic cells exhibited black nuclei. (D) l-Arginine–induced pancreatitis was evaluated 72 hours after induction. Pancreata and lungs were removed for morphological analysis by H&E. Note the appearance of focal necrosis in the pancreata of both groups. (E) Serum was removed for amylase and lipase evaluation at the indicated time points. Note the significant release of amylase and lipase into the serum in relaΔ/Δ mice. Lung inflammation was evaluated as described in Methods. Values are mean ± SD for independent animals (n = 5). *P < 0.05 versus relaflox/flox. Original magnification, ×50 (A, inset); ×200 (A and D); ×100 (C, inset); ×100 (C).