Inflammatory cells regulate p53 and caspases in acute pancreatitis.
The inflammatory response during pancreatitis regulates necrotic and apoptotic rates of parenchymal cells. Neutrophil depletion by use of anti-polymorphonuclear serum (anti-PMN) increases apoptosis in experimental pancreatitis but the mechanism has not been determined. Our study was designed to investigate signaling mechanisms in pancreatic parenchymal cells regulating death responses with neutrophil depletion. Rats were neutrophil depleted with anti-PMN treatment. Then cerulein pancreatitis was induced, followed by measurements of apoptosis signaling pathways. There was greater activation of executioner caspases-3 in the pancreas with anti-PMN treatment compared with control. There were no differences between these groups of animals in mitochondrial cytochrome c release or in activities of initiator caspase-8 and -9. However, there was greater activation of caspase-2 with anti-PMN treatment during cerulein pancreatitis. The upstream regulation of caspases-2 includes p53, which was increased; the p53 negative regulator, Mdm2, was decreased by anti-PMN treatment during cerulein pancreatitis. In vitro experiments using isolated pancreatic acinar cells a pharmacological inhibitor of Mdm2 increased caspase-2/-3 activities, and an inhibitor of p53 decreased these activities during cholecystokinin-8 treatment. Furthermore, experiments using the AR42J cell line Mdm2 small interfering RNA (siRNA) increased caspase-2/-3 activities, and p53 siRNA decreased these activities during cholecystokinin-8 treatment. These results suggest that during acute pancreatitis the inflammatory response inhibits apoptosis. The mechanism of this inhibition involves caspase-2 and its upstream regulation by p53 and Mdm2. Because previous findings indicate that promotion of apoptosis decreases necrosis and severity of pancreatitis, these results suggest that strategies to inhibit Mdm2 or activate p53 will have beneficial effects for treatment of pancreatitis.
Veterans Affairs Greater Los Angeles Healthcare System and Univ. of California at Los Angeles, 11301 Wilshire Blvd., Bldg. 258, Rm. 340, Los Angeles, CA 90073, USA.
Yuji
Y
Nakamura
Jae Hyuk
JH
Do
Jingzhen
J
Yuan
Irina V
IV
Odinokova
Olga
O
Mareninova
Anna S
AS
Gukovskaya
Stephen J
SJ
Pandol
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D002108:Ceruletide / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D009336:Necrosis; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D002108:Ceruletide; D045304:Cytochromes c; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2; C490359:Casp2 protein, rat; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases