Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis.
Activation of the transcription factor NF-kappaB/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-kappaB/Rel and suggest multidimensional roles of NF-kappaB/Rel in different cells and contexts during inflammation.
Algül
Hana
H
Second Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Treiber
Matthias
M
Lesina
Marina
M
Nakhai
Hassan
H
Saur
Dieter
D
Geisler
Fabian
F
Pfeifer
Alexander
A
Paxian
Stephan
S
Schmid
Roland M
RM
D000818:Animals; D001483:Base Sequence; D016923:Cell Death; D002108:Ceruletide / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010195:Pancreatitis / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017384:Sequence Deletion; D051996:Transcription Factor RelA / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C000612141:REG3A protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C490253:Reg3b protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D002108:Ceruletide