Pancreatic STAT3 Protects Mice against Caerulein-Induced Pancreatitis via PAP1 Induction
Pancreatic STAT3 Protects Mice against Caerulein-Induced Pancreatitis via PAP1 Induction
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DOI：
10.1016/j.ajpath.2012.08.038
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发表时间：
2012-12-01
影响因子：
6
通讯作者：
Takehara, Tetsuo
中科院分区：
文献类型：
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作者：
Shigekawa, Minoru;Hikita, Hayato;Takehara, Tetsuo
信号转导和转录激活因子3(STAT3)是一种转录因子，控制细胞存活、增殖和分化以及组织炎症等多个基因的表达。然而，胰腺STAT3在急性胰腺炎中的意义尚不清楚。我们将STAT3(FLOX/FLOX)小鼠与Pdx1启动子Cre转基因小鼠杂交，获得了条件性STAT3基因敲除小鼠(STAT3(Delta/Delta))。野生型小鼠给予雨蛙素后3h即可激活胰腺STAT3，诱发急性胰腺炎，7d内即可完全恢复。STAT3(Delta/Delta)组小鼠3h血清淀粉酶、脂肪酶水平及胰腺坏死和炎性细胞浸润的组织学评分明显高于STAT3(FLOX/FLOX)组。与STAT3(FLOX/FLOX)小鼠相比，STAT3(Delta/Delta)小鼠胰腺炎后胰腺恢复明显延迟。尽管STAT3(FLOX/FLOX)小鼠在胰腺中显著产生胰腺炎相关蛋白1(PAP1)，这是一种血清急性时相蛋白，但这种诱导在STAT3(Delta/Delta)小鼠中完全取消。在肝脏中通过流体动力学程序促进PAP1的产生显著抑制胰腺坏死和炎症，并促进STAT3(Delta/Delta)小鼠胰腺的再生和恢复，达到与STAT3(FLOX/FLOX)小鼠相似的水平。综上所述，胰腺STAT3对于PAP1的产生是不可或缺的，该STAT3/PAP1通路在雨蛙素诱导的胰腺炎中起到保护作用。(Am J Pathol2012,181：2105-2113；http://dx.doi.org/10.1016/j.ajpath.2012.08.038)
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(Delta/Delta)) 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(Delta/Delta) mice than in stat3(flox/flox) mice. Pancreatic recovery after pancreatitis was significantly delayed in stat3(Delta/Delta) 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(Delta/Delta) 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(Delta/Delta) 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. (Am J Pathol 2012, 181:2105-2113; http://dx.doi.org/10.1016/j.ajpath.2012.08.038)