Functional analysis of the relevance of Bcl-3 and its interference with STAT3 in acute pancreatitis as an example of inflammation in the gastrointestinal tract

急性胰腺炎（AP）等炎症性疾病的免疫反应是由精细的机制控制的。这些机制的功能失调导致过度的免疫刺激，称为全身性炎症反应综合征（SIRS）。SIRS将胰腺局部损伤与全身并发症联系起来。在上一个资助期内，我们发现IL-6/STAT3信号通路是AP伴SIRS和胰腺炎相关肺损伤的中介。STAT3依赖性SOCS3的表达以负反馈机制调控信号通路。根据我们的初步实验，Bcl-3似乎在激活IL-6/STAT3信号通路方面具有与SOCS3相似的功能。Bcl-3是IkappaB蛋白家族的非典型成员，主要调控NF-kappaB二聚体与DNA的结合。虽然最近的出版物表明Bcl-3在急性炎症反应中干扰STAT3的激活，但其在急性胰腺炎中的作用迄今尚未得到研究。我们的初步结果表明，Bcl-3在实验和人类AP中都有表达。与SOCS3的缺失类似，小鼠Bcl-3基因失活导致胰腺STAT3激活增加，实验性AP加重。在本资助期内，我们将利用转基因小鼠分析Bcl-3及其与STAT3激活的相互作用在AP炎症反应模型中的作用。

The immune response in inflammatory diseases like acute pancreatitis (AP) is controlled by meticulous mechanisms. A dysfunctional regulation of these mechanisms leads to an excessive immune stimulation, termed as systemic inflammatory response syndrome (SIRS). SIRS links the local damage in the pancreas to systemic complications. During the last funding period, we identified the IL-6/STAT3 signaling pathway as a mediator in AP with SIRS and concomitant pancreatitis-associated lung injury. STAT3 dependent expression of SOCS3 regulates the signaling pathway in a negative feedback mechanism. Based on our preliminary experiments, Bcl-3 seems to have a similar function on the activation of the IL-6/STAT3 signaling pathway as SOCS3. Bcl-3, an atypical member of the IkappaB protein family, predominantly regulates binding of NF-kappaB dimers to DNA. While recent publications showed that Bcl-3 is interfering with STAT3 activation in acute inflammatory responses, its role in acute pancreatitis has not been investigated so far. Our preliminary results demonstrate that Bcl-3 is expressed in experimental and human AP. Similar to the loss of SOCS3, genetic inactivation of Bcl-3 in mice leads to an increase of STAT3 activation in the pancreas and an aggravation of experimental AP. In this funding period, we will analyze the role of Bcl-3 and its interaction with STAT3 activation in the inflammatory response model of AP by using genetically modified mice.