p8 improves pancreatic response to acute pancreatitis by enhancing the expression of the anti-inflammatory protein pancreatitis-associated protein I.
p8 is a transcription cofactor whose expression is strongly and rapidly activated in pancreatic acinar cells during the acute phase of pancreatitis. A p8-deficient mouse strain was generated as a tool to investigate its function. Upon induction of acute pancreatitis, myeloperoxidase activity in pancreas and serum concentrations of amylase and lipase were much higher and pancreatic lesions more severe in p8-deficient mice than in wild-type, indicating that p8 expression decreased pancreatic sensitivity to pancreatitis induction. The protective mechanism might involve the pancreatitis-associated protein (PAP I), whose strong induction during pancreatitis is p8-dependent, because administration of anti-PAP I antibodies to rats increased pancreatic inflammation during pancreatitis. In addition, 100 ng/ml PAP I in the culture medium of macrophages prevented their activation by tumor necrosis factor alpha, strongly suggesting that PAP I was an anti-inflammatory factor. Finally, PAP I was able to inhibit NFkappaB activation by tumor necrosis factor alpha, in macrophages and in the AR42J pancreatic acinar cell line. In conclusion, p8 improves pancreatic resistance to inducers of acute pancreatitis by a mechanism implicating the expression of the anti-inflammatory protein PAP I.
Vasseur
Sophie
S
Centre de Recherche INSERM, EMI 0116, 163 Avenue de Luminy, BP172, 13009 Marseille, France.
Folch-Puy
Emma
E
Hlouschek
Verena
V
Garcia
Stephane
S
Fiedler
Fritz
F
Lerch
Markus M
MM
Dagorn
Jean Charles
JC
Closa
Daniel
D
Iovanna
Juan Lucio
JL
D000483:Alleles; D000681:Amylases / Q000097:blood; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000737:chemistry; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000737:chemistry; D015153:Blotting, Western; D002108:Ceruletide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000378:metabolism; D037181:Lectins, C-Type / Q000096:biosynthesis* / Q000737:chemistry; D008049:Lipase / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins; D010179:Pancreas / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000378:metabolism; D010195:Pancreatitis / Q000378:metabolism*; D000073718:Pancreatitis-Associated Proteins; D009195:Peroxidase / Q000378:metabolism; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D011506:Proteins; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014162:Transfection; D014357:Trypsin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000681:Amylases; D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D002108:Ceruletide; D004268:DNA-Binding Proteins; D037181:Lectins, C-Type; D008049:Lipase; D016328:NF-kappa B; D009363:Neoplasm Proteins; D010196:Pancreatic Elastase; D000073718:Pancreatitis-Associated Proteins; D009195:Peroxidase; D011506:Proteins; D014357:Trypsin; D014409:Tumor Necrosis Factor-alpha; C491644:Nupr1 protein, mouse; C109741:Nupr1 protein, rat; C000612141:REG3A protein, human; C490253:Reg3b protein, mouse; C000612144:Reg3b protein, rat