Apoptotic Mechanisms of Peroxisome Proliferator-Activated Receptor-γ Activation in Acinar Cells During Acute Pancreatitis.
OBJECTIVE
The objective of this study was to determine the mechanism by which activation of peroxisome proliferator-activated receptor-γ promotes apoptosis of acinar cells in pancreatitis.


METHODS
AR42j cells pretreated with the peroxisome proliferator-activated receptor-γ agonist pioglitazone were activated by cerulein as an in vitro model of acute pancreatitis. Inflammatory cytokines and amylase were detected by enzyme-linked immunosorbent assay. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis was measured by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Activity of caspases was determined. Bax and Bcl-2 levels were assayed by Western blot.


RESULTS
Cytokines, amylase, and cellular proliferation decreased in pioglitazone-pretreated cells. Pioglitazone increased the activity of caspases 3, 8, and 9 in cerulein-activated AR42j cells as well as in the pancreas of rats 3 hours after induction of severe acute pancreatitis. Acinar cell apoptosis was induced by reducing the mitochondrial membrane potential in the pioglitazone group. Pioglitazone increased expression of proapoptotic Bax proteins and decreased antiapoptotic Bcl-2 in cerulein-induced AR42j cells and decreased Bcl-2 levels in pancreatic tissue of severe acute pancreatitis rats 1 and 3 hours after induction.


CONCLUSIONS
Pioglitazone may promote apoptosis of acinar cells through both intrinsic and extrinsic apoptotic pathways in acute pancreatitis.
From the Departments of *Gastroenterology and †Central Laboratory, Songjiang Hospital Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
Ping
P
Xu
Xiao-Li
XL
Lou
Cheng
C
Chen
D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism*; D000208:Acute Disease; D000681:Amylases / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002108:Ceruletide; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D000077205:Pioglitazone; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D045162:Thiazolidinediones / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; C494828:Bax protein, rat; D016207:Cytokines; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D045162:Thiazolidinediones; D051028:bcl-2-Associated X Protein; D002108:Ceruletide; D000681:Amylases; D020169:Caspases; D000077205:Pioglitazone