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

炎症性疾病如急性胰腺炎(AP)的免疫反应受到精细机制的控制。这些机制的失调调节导致过度的免疫刺激，称为全身性炎症反应综合征(SIRS)。SIRS将胰腺的局部损害与全身并发症联系起来。在上一次资助期间，我们发现IL-6/STAT3信号通路在AP合并SIRS和伴发胰腺炎相关肺损伤中起中介作用。依赖STAT3的SOCS3的表达以负反馈机制调节信号通路。根据我们的初步实验，在激活IL-6/STAT3信号通路方面，Bcl3似乎与SOCS3具有相似的功能。BCL-3是IkappaB蛋白家族中的一个非典型成员，主要调控核因子-kappaB二聚体与DNA的结合。虽然最近的文献表明，在急性炎症反应中，Bcl3干扰STAT3的激活，但到目前为止，它在急性胰腺炎中的作用尚未被研究。我们的初步结果表明，Bcl3在实验性AP和人类AP中有表达。与SOCS3基因失活类似，小鼠胰腺中Bcl3基因失活导致胰腺中STAT3活性增加，并加重实验性AP。在这一资助时期，我们将利用转基因小鼠来分析Bcl3在AP炎症反应模型中的作用及其与STAT3激活的相互作用。

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.