Pancreatic STAT3 protects mice against caerulein-induced pancreatitis via PAP1 induction.
The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that controls expressions of several genes involved in cell survival, proliferation and differentiation, and tissue inflammation. However, the significance of pancreatic STAT3 in acute pancreatitis remains unclear. We generated conditional STAT3 knockout (stat3(Δ/Δ)) mice by crossing stat3(flox/flox) mice with Pdx1-promoter Cre transgenic mice. Caerulein administration activated pancreatic STAT3 and induced acute pancreatitis as early as 3 hours in wild-type mice, and full recovery from the induced pancreatic injury was observed within 7 days. The levels of serum amylase and lipase and histologic scores of pancreatic necrosis and inflammatory cell infiltration were significantly higher at 3 hours in stat3(Δ/Δ) mice than in stat3(flox/flox) mice. Pancreatic recovery after pancreatitis was significantly delayed in stat3(Δ/Δ) mice compared with stat3(flox/flox) mice. Although stat3(flox/flox) mice had marked production in the pancreas of pancreatitis-associated protein 1 (PAP1), a serum acute phase protein, this induction was completely abrogated in stat3(Δ/Δ) mice. Enforced production of PAP1 by a hydrodynamic procedure in the liver significantly suppressed pancreatic necrosis and inflammation and also promoted pancreatic regeneration and recovery in stat3(Δ/Δ) mice to levels similar to those observed in stat3(flox/flox) mice. In conclusion, pancreatic STAT3 is indispensable for PAP1 production, and this STAT3/PAP1 pathway plays a protective role in caerulein-induced pancreatitis.
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
Minoru
M
Shigekawa
Hayato
H
Hikita
Takahiro
T
Kodama
Satoshi
S
Shimizu
Wei
W
Li
Akio
A
Uemura
Takuya
T
Miyagi
Atsushi
A
Hosui
Tatsuya
T
Kanto
Naoki
N
Hiramatsu
Tomohide
T
Tatsumi
Kiyoshi
K
Takeda
Shizuo
S
Akira
Tetsuo
T
Takehara
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002108:Ceruletide; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology*; D010195:Pancreatitis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000073718:Pancreatitis-Associated Proteins; D050796:STAT3 Transcription Factor / Q000378:metabolism*
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D002108:Ceruletide